CN108135967B - Composition with penetration enhancer for drug delivery - Google Patents

Composition with penetration enhancer for drug delivery Download PDF

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CN108135967B
CN108135967B CN201680057343.9A CN201680057343A CN108135967B CN 108135967 B CN108135967 B CN 108135967B CN 201680057343 A CN201680057343 A CN 201680057343A CN 108135967 B CN108135967 B CN 108135967B
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composition
certain embodiments
optionally substituted
alkynyl
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CN108135967A (en
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丹尼尔·S·克哈奈克
杨蓉
莉莉·云·林
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Childrens Medical Center Corp
Massachusetts Institute of Technology
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Childrens Medical Center Corp
Massachusetts Institute of Technology
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
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    • C08G65/3353—Polymers modified by chemical after-treatment with organic compounds containing phosphorus containing oxygen in addition to phosphorus
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Abstract

The present invention provides compositions and methods for delivering therapeutic agents across a barrier. The composition includes a therapeutic agent (e.g., an antimicrobial agent, an antibiotic, or an anesthetic agent), a permeation enhancer that increases the flux of the therapeutic agent across the barrier, and a matrix forming agent. The matrix forming agent forms a gel for drug delivery at a suitable gelling temperature and rheology, and in some cases, the gelling temperature and rheology are not significantly altered from the gelling temperature and rheology of the composition without the permeation enhancer. The invention also provides matrix forming agents and compositions thereof. Such compositions are particularly useful for treating otitis media. Methods of treatment, methods of delivery, and kits for the compositions described herein are also provided.

Description

Composition with penetration enhancer for drug delivery
RELATED APPLICATIONS
This application claims priority from U.S. provisional application u.s.s.n.62/201,199 filed 2015, 8, 5, as filed pursuant to 35u.s.c. § 119(e), which is incorporated herein by reference.
Background
In the united states, between 1200 and 1600 million physician visits per year are due to Otitis Media (OM), making it the most common disease of children for special treatment. [1] Acute om (aom) has a 90% prevalence within the first 5 years of life [2], and 90% to 95% of all children in the united states have at least one documented middle ear effusion before the age of 2. [3] A percentage of 25% of all prescriptions written for children are used to treat acute otitis media. Recurrence of this disease is also dramatic, with one third of all children in the united states occurring 6 or more times before age 7. [4] Furthermore, epidemiological studies have shown an increased prevalence of relapsing OM in children, particularly infants. [5] The incidence of OM in children in other industrialized countries is similar to that in the united states. In developing countries, OM remains a significant cause of mortality in children due to the occurrence of chronic suppurative otitis media, which often leads to permanent hearing sequelae, and estimated global over 25,000 deaths due to intracranial complications. [6]
Acute OM is the most common reason for antimicrobial prescription in american children, and is believed to contribute in part to the continuing increase in antibiotic resistance in pathogenic bacteria due to the high prevalence and multiplicity of the disease. Despite the success in reducing antimicrobial use in children by about 25% over the past decade, the improvement in antimicrobial resistance continues.
Current treatment for ear infections consists of systemic oral antibiotics, which are treatments requiring multiple doses of 5 to 10 days and systemic exposure to antibiotics. The increase in antibiotic resistance coupled with the multifactorial disease of OM creates difficulties in the diagnosis and treatment of OM. In addition, current treatments suffer from a number of disadvantages, including patient compliance problems caused by gastrointestinal side effects, lack of effective concentrations of drugs at the site of infection and the potential for opportunistic infections. Even after the acute infectious condition subsides (usually within 72 hours), the root cause of the infection may persist and exceed the remainder of the treatment, even up to 2 months. Therefore, it is important to make compliance with the physician's prescription to prevent recurrence of infection.
Direct local sustained delivery of an active therapeutic agent to the middle ear to treat OM can allow for much higher drug concentrations in the middle ear than from systemic administration while minimizing systemic exposure and its side effects. However, the Tympanic Membrane (TM) although only 10 cell layers thick provides a barrier that is largely impermeable to all but the smallest, moderately hydrophobic molecules. Although the thinnest skin layer, it is still a barrier to trans-tympanic diffusion. Therefore, direct treatment of middle ear infections is problematic. The shortcomings of current treatments of otic disorders (e.g., middle ear infections) indicate the need for new treatments that are non-invasive and direct acting.
Summary of The Invention
Provided herein are compositions and methods directed to non-invasive treatment of tympanitis (OM) with sustained drug flux across the Tympanic Membrane (TM) (see, e.g., fig. 1). Chemical Penetration Enhancers (CPEs), which are commonly used for transdermal delivery, can achieve such trans-tympanic flux. In certain embodiments, a single application of an optimized formulation may provide a high antibiotic concentration in the middle ear, thereby allowing eradication of bacterial otitis media without the disadvantages of oral treatment. Such formulations may also be used to treat other otic disorders requiring drug delivery across the tympanic membrane.
Typical OM treatment consists of a 10 day course of a broad spectrum oral antibiotic. The widespread use of systemic antibiotics for such high prevalence and recurrent disease is believed to result in part in the increased persistent antibiotic resistance seen in pathogenic bacteria in the nasopharynx. In most cases, antibiotic-resistant infections (e.g., pneumonia, skin, soft tissue and gastrointestinal infections) require long and/or more expensive treatments, prolonged hospital stays, require additional physician visits and healthcare services, and result in greater disability and death compared to infections that can be readily treated with antibiotics. Compliance with multiple dose regimens may also be difficult in certain parts of the world. Compliance and antibiotic resistance may also be more problematic in the long-term prevention of relapsing OM. Effective sustained local treatment can address compliance issues, affect development of drug resistance and chronic suppurative otitis media, and reduce the need for tympanostomy tube placement (a device implanted in the TM to enhance recurrent OM middle ear drainage). [8]
TM is a three-layered membrane, the outer layer of which is a layered squamous keratinized epithelium that is continuous with the skin of the external auditory canal. The innermost layer is a simple cuboidal mucosal epithelium. Interposed between these epithelia are layers of fibroelastic connective tissue and associated blood vessels and nerves. Human TM is only about 100 μm thick, but due to its keratin and lipid rich stratum corneum, the outer epithelium of 6 to 10 cell layers forms an impermeable barrier against all but the smallest lipophilic molecules. [11]
Local sustained drug delivery directly to the target tissue has a number of advantages over systemic administration, including less adverse systemic effects, use of lower amounts of drug, potentially better therapeutic results, and cost reduction. The impermeability of TM is a central challenge for the development of topical treatments.
Chemical Permeation Enhancers (CPEs) are used to safely increase small molecule flux in transdermal drug delivery. Several are FDA approved for use in humans. These agents are typically surfactants comprising a heterogeneous group of amphiphilic organic molecules with a hydrophilic head and a hydrophobic tail. Several classes of surfactants have been investigated. Surfactants reversibly modify lipids by adsorbing at the interface and removing water soluble agents that act as plasticizers. Cationic surfactants are known to increase permeate flux more than anionic surfactants, which in turn increases permeability more than nonionic surfactants. A wide range of non-surfactant chemical enhancers (e.g., terpenes) have also been used for mechanisms of action, including protein denaturation within and between keratinocytes, and/or modification or disruption of lipids leading to increased lipid bilayer fluidity.
In the compositions provided herein, the therapeutic agent and penetration enhancer are combined with a matrix-forming agent to form a composition that forms a hydrogel under suitable conditions. Such conditions may include exposure to body heat (e.g., in the ear canal) during administration, or after mixing of the two components of the composition or the matrix forming agent. A matrix forming agent is a compound or mixture of compounds that forms a gel after application. The composition is typically a liquid at ambient conditions, however, once administered to a subject, the matrix forming agent or combination of matrix forming agents causes a phase change to the hydrogel. Hydrogels have a highly porous structure, which allows for loading of drugs and other small molecules, and subsequent elution of the drug out of the gel creates high local concentrations in the surrounding tissue over a long period of time. In certain embodiments, the drug is loaded in a liquid composition. Hydrogels can conform to the shape of and adhere to the surface to which they are applied, and are often biocompatible.
For the compositions provided herein, the combination of a penetration enhancer with a matrix forming agent and a therapeutic agent provides a composition that: therapeutic agent flux is increased and the properties of the resulting hydrogel are improved or not significantly impaired relative to a hydrogel formed from the composition in the absence of a permeation enhancer. For example, the phase transition temperature of a composition with a permeation enhancer may be lower, or even higher, than a composition without a permeation enhancer, and still fall within a useful range for forming a hydrogel after exposure to a biological surface (e.g., a phase transition temperature of about 0 ℃ to about 37 ℃). As another example, the storage modulus (storage modulus) and/or loss modulus (loss modulus) of a composition with a permeation enhancer may be about the same (e.g., within about 20%) as a composition without a permeation enhancer, or the storage modulus of a composition with a permeation enhancer may be higher than a composition without a permeation enhancer. As another example, the storage modulus and/or loss modulus of a composition with a permeation enhancer may be about the same (e.g., within about 20% or 3kPa, whichever is greater) as a composition without a permeation enhancer, or the storage modulus of a composition with a permeation enhancer may be higher than a composition without a permeation enhancer. For the compositions provided herein, the combination of a penetration enhancer with a matrix forming agent and a therapeutic agent provides such compositions: which has increased therapeutic agent flux and other improved properties (including but not limited to extended drug release, adhesion of the composition to the tympanic membrane over time, degradation, or a combination thereof), and the properties of the resulting hydrogel are improved or not significantly impaired relative to a hydrogel formed from the composition in the absence of a permeation enhancer.
In one aspect, provided herein is a composition comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a polymer;
wherein:
the composition forms a gel at a temperature above the phase transition temperature; and is
A phase transition temperature of less than about 37 ℃;
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) at a temperature of about 37 ℃, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition; and
(iii) the composition has a loss modulus of from about 80% to about 120% of the loss modulus of the reference composition at a temperature of about 37 ℃;
wherein the reference composition is the composition in the absence of (b) a penetration enhancer or a combination of penetration enhancers.
In one aspect, provided herein is a composition comprising:
(a) A therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a polymer;
wherein:
the composition forms a gel at a temperature above the phase transition temperature; and is
A phase transition temperature of less than about 37 ℃;
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) a storage modulus of the composition at a temperature of about 37 ℃ that is greater than about 15% or greater than about 500Pa, whichever is less, of a storage modulus of a reference composition; and
(iii) the composition has a loss modulus of from about 15% to about 150% of the loss modulus of the reference composition at a temperature of about 37 ℃;
wherein the reference composition is the composition in the absence of (b) a penetration enhancer or a combination of penetration enhancers.
In certain embodiments, condition (i) is satisfied in that the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃. In certain embodiments, condition (ii) is satisfied, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of a reference composition. In certain embodiments, condition (ii) is satisfied, i.e., the composition has a storage modulus that is greater than about 15% or greater than about 500Pa, whichever is less, of the storage modulus of a reference composition. In certain embodiments, condition (ii) is satisfied, i.e., the composition has a storage modulus that is greater than about 15% or greater than about 1000Pa, whichever is less, of the storage modulus of a reference composition. In certain embodiments, condition (iii) is satisfied, i.e., the composition has a loss modulus from about 80% to about 120% of the loss modulus of the reference composition. In certain embodiments, condition (iii) is satisfied, i.e., the composition has a loss modulus from about 15% to about 150% of the loss modulus of the reference composition. In certain embodiments, both conditions (i) and (ii) are satisfied. In certain embodiments, both conditions (ii) and (iii) are satisfied. In certain embodiments, both conditions (i) and (iii) are satisfied. In certain embodiments, each of conditions (i), (ii), and (iii) is satisfied.
In certain embodiments, the polymer is biodegradable. In certain embodiments, the polymer is a copolymer. In certain embodiments, the copolymer is biodegradable or comprises a biodegradable monomer. In certain embodiments, the copolymer is a block copolymer. In certain embodiments, the copolymer comprises at least one hydrophobic monomer block. In certain embodiments, the copolymer comprises at least one hydrophobic monomer block and at least one non-hydrophobic monomer block.
In certain embodiments, the copolymer comprises a copolymer of a vinyl polymer (e.g., PE, PVC, PVDC, PS), a polyacrylate (e.g., polyacrylic polymethacrylic acid), a polyether (e.g., PEO, PPO, POM), a fluoropolymer (e.g., PTFE), a polysiloxane (e.g., PDMS), a polysaccharide (e.g., cellulose, dextran, hyaluronic acid, chitosan), a polyester (e.g., PET, polyhydroxyalkanoate (e.g., PHB)), a polyamide (e.g., poly (lactic acid), poly (glycolic acid)), a polyphosphate, polyurethane, or polycarbonate, or a combination thereof. In certain embodiments, the copolymer comprises a copolymer of polyethylene oxide, polypropylene oxide, a poloxamer, poloxamer 407, poloxamer 188, poloxamine, methylcellulose, hydroxypropylmethylcellulose, ethyl (hydroxyethyl) cellulose, xyloglucan, cellulose, acetate phthalate, latex, poly (acrylic acid), an N-isopropylacrylamide-based system, hyaluronic acid, chitosan, dextran, or gellan gum, or a derivative thereof, or a combination thereof. In certain embodiments, the copolymer comprises a poloxamer. In some embodiments, the copolymer comprises poloxamer 407. In certain embodiments, the copolymer comprises a phosphate ester monomer. In certain embodiments, the copolymer comprises a poloxamer and a phosphate ester monomer.
In certain embodiments, the composition has a high degree of hydrophobicity. In certain embodiments, the composition is optically clear.
In certain embodiments, the phase transition temperature of the composition is at or below the body temperature of the subject. In certain embodiments, the phase transition temperature of the composition is from about 10 ℃ to about 40 ℃. In certain embodiments, the phase transition temperature of the composition is from about 20 ℃ to about 40 ℃. In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of the same composition without the permeation enhancer plus about 5 ℃.
In certain embodiments, the compositions are useful for treating diseases. In some embodiments, the composition is used to treat an infectious disease. In some embodiments, the composition can be used to treat an otic disorder (e.g., the barrier is the tympanic membrane). In some embodiments, the composition can be used to treat otitis media.
In another aspect, provided herein is a composition for treating an infectious disease or an otic disease, comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) A matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a copolymer comprising a phosphate ester monomer.
The therapeutic agent may be an antibiotic agent, anesthetic agent, anti-inflammatory agent, analgesic agent, anti-fibrotic agent, anti-sclerosing agent, or anticoagulant agent. In certain embodiments, the therapeutic agent is an antibiotic selected from the group consisting of: ciprofloxacin, cefuroxime, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefodipineNylon, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, penicillins, piperacillin, ticarcilon, sulfamoyl, sulfadiazine, sulfasalazine, sulfaisoethazine, sulfafurilamide, cefazolidone, cefepime, cefixime, enoxime, ceftioxime, ceftriaxone, ceftizoxime, ceft
Figure BDA0001614314770000071
Azole, trimethoprim and trimethoprim-sulfamethoxazole
Figure BDA0001614314770000072
And (3) azole. In some embodiments, the antibiotic is ciprofloxacin. In some embodiments, the antibiotic is amoxicillin, azithromycin, cefuroxime, ceftriaxone, or trimethoprim. In some embodiments, the antibiotic is levofloxacin.
The penetration enhancer may be a surfactant, terpene, amino amide, amino ester, azide-containing compound, alcohol, or anesthetic. The penetration enhancer may be a surfactant, terpene, amino amide, amino ester, azide-containing compound, alcohol, pyrrolidone, sulfoxide, fatty acid, or anesthetic. In some embodiments, the penetration enhancer is a surfactant (e.g., cationic surfactant, anionic surfactant, nonionic surfactant). In some embodiments, the penetration enhancer is a terpene. In some embodiments, the composition comprises a surfactant penetration enhancer and a terpene penetration enhancer.
In certain embodiments, the penetration enhancer is sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethylammonium bromide, cetyl chlorideRadical pyridine
Figure BDA0001614314770000073
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl chembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure BDA0001614314770000074
Chlorinated dodecyl pyridine
Figure BDA0001614314770000075
Cetyl pyridinium chloride
Figure BDA0001614314770000076
Benzyl dimethyldodecyl ammonium chloride, benzyl dimethylmyristyl ammonium chloride, benzyl dimethylstearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. In certain embodiments, the permeation enhancer is sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, or polysorbate 80. In some embodiments, the permeation enhancer is sodium lauryl sulfate.
In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate, sorbitan monooleate (sorbitan monooleate), octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000 Molecular Weight (MW)), or octyldodecanol.
In certain embodiments, the penetration enhancer is an azone-like compound. In certain embodiments, the penetration enhancer is a compound similar to an azone (e.g., laurocapram) of the formula:
Figure BDA0001614314770000081
in certain embodiments, the permeation enhancer is a piperazine-containing compound. In certain embodiments, the penetration enhancer is 1-benzyl-4- (2- ((1, 1-biphenyl) -4-yloxy) ethyl) piperazine.
In certain embodiments, the penetration enhancer is a terpene (e.g., limonene). In certain embodiments, the penetration enhancer is limonene, cymene, pinene, camphor, menthol, camphor, phellone, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, beta-caryophyllene, eucalyptol (eucakytol), hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, or ethylpiperazine carboxylate. In some embodiments, the penetration enhancer is limonene.
In certain embodiments, the penetration enhancer is bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomecaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, piperocaine, or tricaine. In some embodiments, the penetration enhancer is bupivacaine.
In some embodiments, the penetration enhancer is a combination of a surfactant and a terpene. In some embodiments, the penetration enhancer is a combination of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer is a combination of a surfactant selected from the group consisting of: sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, and polysorbate 80. In some embodiments, the penetration enhancer is a combination of a surfactant selected from the group consisting of: sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20 and polysorbate 80. In some embodiments, the permeation enhancer is sodium lauryl sulfate, limonene, or bupivacaine, or a combination thereof. In some embodiments, the penetration enhancer is a combination of sodium lauryl sulfate and limonene. In some embodiments, the penetration enhancer is a combination of sodium lauryl sulfate, limonene, and bupivacaine.
The composition may also comprise additional therapeutic agents, including anti-inflammatory agents (e.g., dexamethasone), anesthetic agents (e.g., bupivacaine), or beta-lactamase inhibitors. In some embodiments, the therapeutic agent or additional therapeutic agent also serves as a penetration enhancer. In some embodiments, an aminoamide (e.g., bupivacaine) or aminoester (e.g., tetracaine) local anesthetic is used as both a penetration enhancer and a therapeutic agent. In some embodiments, the compositions comprise an aminoamide (e.g., bupivacaine) or aminoester (e.g., tetracaine) local anesthetic that acts as both a penetration enhancer and a therapeutic agent, and do not comprise an additional therapeutic agent. In some embodiments, the composition comprises bupivacaine that acts as both a penetration enhancer and a therapeutic agent, and does not comprise an additional therapeutic agent.
In certain embodiments, the therapeutic agent comprises from about 0.01% to about 10% of the composition. In certain embodiments, the percentage weight of the penetration enhancer in the composition is from about 0.1% to about 1%, from about 1% to about 3%, or from about 3% to about 10%. In certain embodiments, the percentage weight of matrix forming agent in the composition is from about 1% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, or from about 40% to about 50%. Unless otherwise indicated, percent compositions herein refer to the weight of the components per volume of the composition.
In certain embodiments, the matrix forming agent comprises a monomer of formula (M):
Figure BDA0001614314770000091
in certain embodiments, the matrix forming agent is a block copolymer of formula (I):
Figure BDA0001614314770000092
for formulas (M) and (I):
each occurrence of Y is independently-R1or-L2R2；
R1Independently for each occurrence is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally sparked aryl, or optionally substituted heteroaryl;
L2independently for each occurrence is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
R2Independently for each occurrence is optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORb、-N(Rb)2Or an oxygen protecting group;
R3each occurrence is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -ORbor-N (R)b)2；
RbIndependently for each occurrence is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two RbTogether with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring;
G1and G2Each independently is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substitutedA substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate, or an oxygen protecting group; and is
p, q, r, s and t are each independently integers, inclusive, from 0 to 200, where the sum of p and t is at least 1 and the sum of q, r and s is at least 1.
In certain embodiments, the matrix forming agent comprises a block copolymer comprising poloxamer 407(P407) or similar analogs linked through their terminal hydroxyl groups to a polyphosphate (PPE) block (see fig. 7). The hydrophobic PPE side chains may increase hydrogel modulus, reduce hydrogel erosion in situ, enhance micelle stacking during gelation, reduce gelation temperature, or a combination thereof. The thermal responsiveness and bioadhesive characteristics of the composition can be adjusted by the choice of side chains (e.g., alkyl side chains, acryl side chains).
In another aspect, provided herein is a matrix-forming agent or combination of matrix-forming agents of formula (Γ):
Figure BDA0001614314770000101
wherein: each occurrence of Y is independently-R1or-L2R2；
R1Each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2independently for each occurrence is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
R2independently for each occurrence is optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR b、-N(Rb)2Or an oxygen protecting group;
R3Aeach occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenylOptionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -ORbor-N (R)b)2；
RbEach occurrence is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or both RbTogether with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring;
G1Aand G2AEach independently is hydrogen, halogen, optionally substituted amine, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate, or an oxygen protecting group; and is
p, q, r, s and t are each independently integers, inclusive, from 0 to 200, where the sum of p and t is at least 1 and the sum of q, r and s is at least 1.
In another aspect, provided herein is a composition comprising a matrix-forming agent or combination of matrix-forming agents of formula (Γ):
Figure BDA0001614314770000111
In another aspect, provided herein is a method for treating an infectious disease comprising administering to a subject in need thereof a composition comprising a therapeutic agent, a penetration enhancer, and a matrix-forming agent as described herein.
In another aspect, provided herein is a method for treating an otic disorder comprising administering to a subject in need thereof a composition comprising a therapeutic agent, a penetration enhancer, and a matrix forming agent as described herein. In certain embodiments, the composition is administered into the ear canal or to the tympanic membrane. In certain embodiments, the disease is otitis media. In certain embodiments, the disease is an ear infection. In certain embodiments, the disease is a bacterial infection (e.g., infection by haemophilus influenzae (h. influenza), streptococcus pneumoniae (s. pneumoconiae), or moraxella catarrhalis).
In another aspect, provided herein is a method for eradicating a biofilm comprising administering to a subject in need thereof, or contacting a biofilm with a composition described herein.
In another aspect, provided herein is a method for inhibiting biofilm formation, comprising administering to a subject in need thereof, or contacting a surface with a composition described herein.
In another aspect, provided herein is a method for delivering a composition described herein, the method comprising administering the composition into the ear canal of a subject, where the composition contacts a surface of the tympanic membrane. The composition may be administered using an eye dropper (eye dorper), syringe, double barrel syringe or catheter (e.g., vascular catheter).
In another aspect, provided herein is a kit (kit) comprising a container, a composition described herein, and instructions for administering the composition to a subject in need thereof. The kit can further comprise a device for administering the composition to a subject, such as a dropper, a syringe, a catheter, a dual syringe, or a combination thereof.
The compositions, composition components (e.g., matrix forming agents, therapeutic agents, and penetration enhancers), methods, kits, and uses of the present disclosure may also incorporate any of the features described in: khoo et al, Biomaterials, (2013)34, 1281-8; U.S. patent nos. 8,822,410; U.S. patent application No.12/993,358 filed on 19/5/2009; U.S. patent application No.11/734,537 filed on 12.4.2007; WIPO patent application No. pct/US2009/003084, filed on 19.5.2009; and WIPO patent application No. pct/US2007/009121, filed on 12.4.2007, each of which is incorporated herein by reference.
The details of certain embodiments of the invention are set forth in the detailed description of certain embodiments, below. Other features, objects, and advantages of the invention will be apparent from the definition, examples, drawings, and claims.
Brief Description of Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
FIG. 1: a trans-tympanic antibiotic delivery regimen.
Fig. 2A to 2D: image of Tympanic Membrane (TM): (2A) normal untreated TM; (2B) TM with otitis media; (2C) TM with ciprofloxacin-containing gel; (2D) TM with a gel comprising ciprofloxacin and a penetration enhancer. Scale bar 20 μm.
FIG. 3: a graph showing enhanced TM flux from gels containing permeation enhancers is shown. (P407 is poloxamer 407, ciprofloxacin, and 3CPE refers to 1% sodium lauryl sulfate, 0.5% bupivacaine, 2% limonene).
FIG. 4: a graph showing the Auditory Brainstem Response (ABR) threshold shift following administration of 18% poloxamer 407(P407) containing a chemical penetration enhancer. Horizontal lines indicate no change.
FIG. 5: linear oscillatory shear rheological measurements (100 rads) of storage and loss moduli of 18% P407 with 1% sodium dodecyl sulfate, 2% limonene, and 0.5% bupivacaine (3CPE) with 18% P407 -11% strain, 1 ℃ minute-1)。
FIG. 6: isobolograms showing CPE B concentration relative to CPE a concentration and indicating conditions of synergy and antagonism between CPEs.
Fig. 7A to 7C: (7A) and (3) synthesis of a poloxamer-polyphosphate block copolymer. (7B) Exemplary pendant phosphate groups for modulating hydrophobicity. (7C) Exemplary phosphate groups for enhancing bioadhesion.
FIG. 8: crosslinkable Hyaluronic Acid (HA) derivatives. The upper diagram: an aldehyde derivative of HA. The following figures: HA hydrazide derivatives.
FIG. 9: P407-PBP, poloxamer 407-poly (butoxy) phosphate and FTIR of the starting material P407. Additional stretches (stretch) indicating the addition of butoxyphosphate monomers are shown.
FIG. 10: alone (polymer) with 1% sodium lauryl sulfate(SDS), linear oscillatory shear rheological measurements (100 rads) of storage and loss moduli of 18% P407-PBP with 2% Limonene (LIM), with 0.5% bupivacaine (Bup), or with 1% sodium dodecyl sulfate, 2% limonene, and 0.5% bupivacaine (3CPE) (SDS-100)-11% strain, 1 ℃ minute-1)。
FIG. 11: P407-PBP with n-butyl and DP 5. Fig. 11 (a): the chemical structure of P407-polybutylphosphate with n-butyl side groups, and the FTIR spectra of P407 and P407-PBP. Fig. 11 (B): chemical structure of P407-polybutylphosphate with sec-butyl side group and corresponding FTIR spectrum.
Fig. 12 (a): nuclear Magnetic Resonance (NMR) of pentablock copolymer P407-PBP. Fig. 12 (B): the effect of n-butyl phosphate or sec-butyl phosphate and degree of polymerization on the storage modulus and loss shear modulus of 18% aqueous solutions of the P407 derivative as a function of temperature. The polymers tested included: P407-PBP with n-butyl or sec-butyl and a Degree of Polymerization (DP) of 2.5 or 5. Data are mean ± SD, n is 4.
FIG. 13: gelling of an 18% [ P407] aqueous solution. Gelation of the following aqueous solutions as a function of temperature: fig. 13 (a): 18% without CPE [ P407 ]; fig. 13 (B): 3 CPE-18% [ P407 ]; fig. 13 (C): 18% [ P407-PBP ]; and fig. 13 (D): 3 CPE-18% [ P407-PBP ]. Note: 3CPE ═ 2% limonene, 1% SDS, and 0.5% bupivacaine. Data are mean ± SD, n is 4.
FIG. 14: schematic representation of gelation of aqueous solutions of P407-PBP, facilitated by hydrophobic interactions of polyphosphate end groups at elevated temperatures (23 ℃).
FIG. 15: effect of CPE alone and polymer concentration on formulation rheology. Fig. 14 (a): effect of CPE alone on gelation temperature. Fig. 15 (B): effect of CPE alone on storage modulus and loss shear modulus of Cip-18% [ P407-PBP ] solutions at 37 ℃. Fig. 15 (C): influence of the concentration of P407-PBP on the gelation temperature. All formulations contained 3 CPE. Fig. 15 (D): effect of P407-PBP concentration on storage modulus and loss shear modulus at 37 ℃ (dashed line in fig. 15 (B)). Data are mean ± SD, n is 4.
FIG. 16: ex vivo transfer of ciprofloxacin into the receiving chamber through the TM. Hydrogel formulation Cip-3 CPE-18% [ P407-PBP ] was able to achieve high drug flux across the TM. Data are mean ± SD, n is 4.
FIG. 17: representative micrographs of Cip-3 CPE-12% [ P407-PBP ] in the ears of normal and diseased chestnut mice (chinchialla). FIG. 17 (A); hematoxylin and eosin (H & E) stained sections of TM sections without Cip-3 CPE-12% [ P407-PBP ] treatment or healthy TM after treatment with Cip-3 CPE-12% [ P407-PBP ] and TM after 7 days OM. The scale bar represents 12 μm. Fig. 17 (B): h & E stained sections of the umbo-malleus region (umbo-malleus region) without treatment with Cip-3 CPE-12% [ P407-PBP ] or after 7 days OM after treatment with Cip-3 CPE-12% [ P407-PBP ]. The scale bar represents 20 μm.
FIG. 18: in vivo potency, pharmacokinetics, effects on hearing sensitivity and effects on tissue of Cip-3 CPE-12% [ P407-PBP ]. Fig. 18 (a): OM animals (defined as the percentage of non-zero cfu values in the ear fluid aspirates therein) before (day 0) and after receiving Cip-3 CPE-12% [ P407-PBP ] (n ═ 10), ciprofloxacin ear drops (n ═ 5), 1% ciprofloxacin ear drops (n ═ 8) or no treatment (n ═ 10). Day 0 reflects the state immediately prior to administration of the therapeutic agent. P-0.0065, by Fisher's exact test. Fig. 18 (B): time course of bacterial colony forming units (cfu) from ear fluid in animals with OM treated with Cip (n-4), Cip-3 CPE-18% [ P407] (n-5), Cip-3 CPE-12% [ P407-PBP ] (n-10) or untreated (n-10) NTHi. Data are mean ± SD. (for purposes of illustration, Log10 cfu is set to zero instead of minus infinity). Fig. 18 (C): FIG. 18(A) shows the concentration of ciprofloxacin in middle ear fluid of the same animal with time. The black dashed line indicates the MIC of NTHi. The inset is an enlarged drug concentration range of 0 to 10. mu.g/mL. Data are mean ± SD. Fig. 18 (D): ABR threshold shift in response to short sounds (acoustic click) and short (8ms) tone bursts (tone burst) of different frequencies. All data here have had the pre-treatment median threshold subtracted from them. The line through the graph represents the interquartile range of the pre-processing values (n-8). Measurement after application of 200 μ L Cip-3 CPE-12% [ P407-PBP ] formulation was black (n ═ 8): black boxes and inner lines represent interquartile range and median, respectively. The small black squares represent the mean and the crosses represent the range.
FIG. 19: ciprofloxacin cumulative release from Cip and from Cip-18% [ P407], Cip-3 CPE-18% [ P407], Cip-18% [ P407-PBP ] and Cip-3 CPE-18% [ P407-PBP ] at 37C under infinite sink conditions (infinitie sink condition). 2mg ciprofloxacin was included in each gel and solution at time zero. Data are mean ± SD, n is 4.
FIG. 20: 12% [ P407-PBP ] and Cip-3 CPE-12% [ P407-PBP ]. Fig. 20 (a): survival of human fibroblasts (hFB), PC12 cells and keratinocytes (determined by MTS assay) after 1 or 3 days of incubation with 12% [ P407-PBP ] and Cip-3 CPE-12% [ P407-PBP ]. Data are mean ± SD (n ═ 4). Fig. 20 (B): live/dead assay of hFB to confirm the data in FIG. 20(A) by different assays after 1 or 3 days of incubation with 12% [ P407-PBP ] or Cip-3 CPE-12% [ P407-PBP ]. White in the GFP graph indicates live cells, and white in the TRITC graph indicates dead cells. Fig. 20 (C): hFB cell viability was obtained by counting live and dead cells in fig. 20(B) and calculating% cell survival ═ live cells/(live + dead cells). Cell counts were performed using ImageJ. Data are mean ± SD (n ═ 4). For all images, a paired sample t-test was applied.
Fig. 21 (a): penetration enhancement of CPE alone. All curves show the cumulative amount of ciprofloxacin permeating through the TM over time. All solutions were made with 12% P407-PBP, 1% ciprofloxacin, and 1% CPE, which contained no CPE except for the "no CPE" group. Fig. 21 (B): the effect of CPE combined with penetration enhancement. All curves show the cumulative amount of ciprofloxacin permeating through the TM over time. All solutions were made with 12% P407-PBP, 1% ciprofloxacin. In particular, Stearyl Methacrylate (SM) and SDS and Bupivacaine (BUP) are 1.5% SM (solubility limit), 1% SDS, 0.5% BUP; BP and SDS and BUP ═ 1.5% BP (solubility limit), 1% SDS, 0.5% BUP; LIM and SDS and BUP ═ 2% LIM, 1% SDS, 0.5% BUP.
Fig. 22 (a): dose-response curves for SDS, LIM, and BUP. The cumulative amount of ciprofloxacin that permeated through the TM after 48 hours increased with the concentration of CPE in the formulation. All formulations were prepared as follows: 12% P407-PBP, 4% ciprofloxacin, and CPE alone at the corresponding concentration (x-axis). The color point demonstrates penetration with the addition of both CPEs. For example, the point in the SDS map next to the label "BUP" indicates permeation when 1% BUP + 1% SDS is added to the formulation instead of 2% SDS. Fig. 22 (B): trans-tympanic permeation of levofloxacin formulations compared to ciprofloxacin formulations. The levofloxacin free drug solution is 1.5 percent levofloxacin water solution; levo, P407-PBP +3CPE ═ 1.5% levofloxacin, 12% P407-PBP, 1% SDS, 2% LIM, 0.5% BUP; cipro, P407-PBP +3CPE ═ 1% ciprofloxacin, 12% P407-PBP, 1% SDS, 2% LIM, 0.5% BUP; ciprofloxacin solution 1% ciprofloxacin solution in Cipro. Fig. 22 (C): penetration of ciprofloxacin (left) and dexamethasone (right) through the TM over time. 4% Cip-0.1% Dex 4% ciprofloxacin and 0.1% dexamethasone in water; 4% Cip-0.1% Dex-3CPE ═ 4% ciprofloxacin, 0.1% dexamethasone, 1% SDS, 2% LIM, 0.5% BUP; 4% Cip-0.1% Dex-3 CPE-18% [ P407] ═ 4% ciprofloxacin, 0.1% dexamethasone, 1% SDS, 2% LIM, 0.5% BUP, 18% P407.
Fig. 23 (a): streptococcus Pneumoniae (SP) cure rates with ciprofloxacin-3 CPE or a 4% ciprofloxacin preparation of ciprofloxacin-3 CPE-12% [ P407-PBP ], which showed a change in the percentage of infected ears over time. Fig. 23 (B): ciprofloxacin-3 CPE-12% [ P407-PBP ] at different concentrations and Middle Ear Fluid (MEF) ciprofloxacin concentration over time for 1% ciprofloxacin-3 CPE. Fig. 23 (C): ex vivo permeation data for 18% poloxamer 407(P407) formulations of ciprofloxacin-3 CPE-12% [ P407-PBP ] and 4% ciprofloxacin-18% [ P407] at different concentrations.
Detailed description of certain embodiments
Provided herein are compositions and methods for administering a therapeutic agent to a subject via a barrier. In some embodiments, the composition is for administration of a therapeutic agent to an ear of a subject, and the barrier is the tympanic membrane. The compositions and methods allow for the effective delivery of agents to the middle and/or inner ear of a subject. In one aspect, the composition comprises a combination of a penetration enhancer, a therapeutic agent, and a matrix forming agent. The permeation enhancer increases the flux of the therapeutic agent across a barrier (e.g., the tympanic membrane) as compared to the flux of a composition lacking the permeation enhancer. In various aspects, the composition is a single application composition for sustained local delivery of a therapeutic agent across the tympanic membrane. In various aspects, the composition is a multi-application composition for local sustained delivery of a therapeutic agent across the tympanic membrane. The compositions and methods of the present invention are particularly useful for treating otitis media by providing sustained release and delivery of antibiotics to the middle ear.
In one aspect, provided herein is a composition comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or a combination of permeation enhancers, wherein the permeation enhancer or the combination of permeation enhancers increases the flux of the therapeutic agent or the combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or the combination of matrix-forming agents comprises a polymer;
wherein:
the composition forms a gel at a temperature above the phase transition temperature;
a phase transition temperature of less than about 37 ℃; and is
And at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) at a temperature of about 37 ℃, the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition; and
(iii) the composition has a loss modulus of from about 80% to about 120% of the loss modulus of the reference composition at a temperature of about 37 ℃;
wherein the reference composition is the composition in the absence of (b) a penetration enhancer or a combination of penetration enhancers.
In another aspect, provided herein is a composition comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) A permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a polymer;
wherein:
the composition forms a gel at a temperature above the phase transition temperature;
a phase transition temperature of less than about 37 ℃; and is
And at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) a storage modulus of the composition at a temperature of about 37 ℃ that is greater than about 15% or greater than about 500Pa, whichever is less, of a storage modulus of a reference composition; and
(iii) at a temperature of about 37 ℃, the composition has a loss modulus from about 15% to about 150% of the loss modulus of the reference composition;
wherein the reference composition is the composition in the absence of (b) a penetration enhancer or a combination of penetration enhancers.
In certain embodiments, condition (i) is satisfied in that the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃. In certain embodiments, condition (ii) is satisfied, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of a reference composition. In certain embodiments, condition (ii) is satisfied, i.e., the storage modulus of the composition is greater than about 15% or 500Pa, whichever is less, of the storage modulus of the reference composition. In certain embodiments, condition (ii) is satisfied, i.e., the composition has a storage modulus that is greater than about 15% or greater than about 1000Pa, whichever is less, of the storage modulus of a reference composition. In certain embodiments, condition (iii) is satisfied, i.e., the composition has a loss modulus from about 80% to about 120% of the loss modulus of the reference composition. In certain embodiments, condition (iii) is satisfied, i.e., the composition has a loss modulus from about 15% to about 150% of the loss modulus of the reference composition. In certain embodiments, both conditions (i) and (ii) are satisfied. In certain embodiments, both conditions (ii) and (iii) are satisfied. In certain embodiments, both conditions (i) and (iii) are satisfied. In certain embodiments, each of conditions (i), (ii), and (iii) is satisfied.
In certain embodiments, the therapeutic agent is a single therapeutic agent. In certain embodiments, the therapeutic agent is a combination of two or more therapeutic agents (e.g., 2, 3, 4). In certain embodiments, the penetration enhancer is a single therapeutic agent. In certain embodiments, the therapeutic agent is a combination of two or more therapeutic agents (e.g., 2, 3, 4). In certain embodiments, the matrix-forming agent is a single matrix-forming agent. In certain embodiments, the matrix forming agent is a combination of two or more matrix forming agents (e.g., 2, 3, 4). In certain embodiments, the therapeutic agent or penetration enhancer may function as both the therapeutic agent and the penetration enhancer. In certain embodiments, the therapeutic agent may act as both a therapeutic agent and a permeation enhancer. In certain embodiments, the permeation enhancer may function as both a therapeutic agent and a permeation enhancer. In certain embodiments, a local anesthetic may serve as both a therapeutic agent and a permeation enhancer. In certain embodiments, an aminoamide or aminoester local anesthetic may be used as both a therapeutic agent and a penetration enhancer. In certain embodiments, an aminoamide or aminoester local anesthetic may be used as both a therapeutic agent and a penetration enhancer. In certain embodiments, an amino ester local anesthetic may be used as both a therapeutic agent and a penetration enhancer. In certain embodiments, bupivacaine may be used as both a therapeutic agent and a penetration enhancer. In certain embodiments, tetracaine can be used as both a therapeutic agent and a permeation enhancer.
In certain embodiments, the permeation enhancer or combination of permeation enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier as compared to a reference composition (e.g., a composition without the permeation enhancer). In certain embodiments, the permeation enhancer or combination of permeation enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier by a factor of: at least about 1.05 times, at least about 1.10 times, at least about 1.2 times, at least about 1.3 times, at least about 1.4 times, at least about 1.5 times, at least about 1.6 times, at least about 1.7 times, at least about 1.8 times, or at least about 1.9 times. In certain embodiments, the permeation enhancer or combination of permeation enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier by a factor of: at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 10 times, at least about 25 times, at least about 50 times, at least about 100 times, at least about 250 times, at least about 500 times, or at least about 1000 times. In certain embodiments, the permeation enhancer or combination of permeation enhancers is present in an amount effective to increase the flux of the therapeutic agent across the barrier by about 1.5-fold to about 100-fold as compared to the reference composition.
In certain embodiments, the polymer is a copolymer. In some embodiments, the polymer is biodegradable. In certain embodiments, the copolymer is a block copolymer. In certain embodiments, the copolymer comprises at least one hydrophobic monomer block. In certain embodiments, the copolymer is biodegradable or comprises at least one biodegradable block.
As used herein, "hydrophobic" refers to polymers that tend to be water insoluble and fat soluble. As used herein, "highly hydrophobic" refers to polymers having low water solubility and having high lipid solubility. In some embodiments, the hydrophobic polymer comprises hydrophobic side chains. In some embodiments, the highly hydrophobic polymer comprises hydrophobic side chains. Hydrophobic side chains include, but are not limited to, side chains comprising hydrocarbon groups such as: alkyl (e.g., methyl), alkenyl, alkynyl, carbocyclyl, and aryl. The hydrophobic moiety may also include a group selected from heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, and heteroaryl, where the heteroatom-containing group is substantially similar to the hydrocarbyl group (e.g., only 1 or 2 carbons are replaced with heteroatoms). The hydrophobic side chain may comprise a group that is the same as or a derivative of a side chain of a hydrophobic amino acid, including but not limited to glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, aminoisobutyric acid, alloisoleucine, tyrosine, and tryptophan. Non-hydrophobic or hydrophilic polymers are polymers that tend to be soluble in water.
In certain embodiments, the polymer or copolymer comprises a copolymer of a vinyl polymer (e.g., PE, PVC, PVDC, PS), a polyacrylate (e.g., polyacrylic polymethacrylic acid), a polyether (e.g., PEO, PPO, POM), a fluoropolymer (e.g., PTFE), a polysiloxane (e.g., PDMS), a polysaccharide (e.g., cellulose, dextran, hyaluronic acid, chitosan), a polyester (e.g., PET, polyhydroxyalkanoate (e.g., PHB)), a polyamide (e.g., poly (lactic acid), poly (glycolic acid)), a polyphosphate, polyurethane, or polycarbonate, or a combination thereof. In certain embodiments, the copolymer comprises a natural polymer. In some embodiments, the copolymer comprises a copolymer of a polysaccharide, proteoglycan, glycosaminoglycan, collagen, fibrin, gelatin, or a derivative thereof, or a combination thereof.
Exemplary polymer types suitable for use in the polymer or copolymer include, but are not limited to: polyethers (e.g., polyethylene oxide, polypropylene oxide, polyethylene oxide-polypropylene oxide copolymers), poloxamers, poloxamines, celluloses and hemicelluloses (e.g., methylcellulose, hydroxypropyl methylcellulose, ethyl (hydroxyethyl) cellulose, xyloglucan), acetates, phthalates, latexes, polyacrylates (e.g., polyacrylic acid), N-alkylacrylamides (e.g., poly (N-isopropylacrylamide)), hyaluronic acid, chitosan, dextran, and gellan gum, and derivatives thereof. In some embodiments, the polymer or copolymer comprises polyethylene oxide or polypropylene oxide. In some embodiments, the copolymer comprises a polyethylene/polypropylene copolymer or a polyethylene/polypropylene block copolymer. In some embodiments, the copolymer comprises a poloxamer. In some embodiments, the copolymer comprises poloxamer 407, poloxamer 188, poloxamine, poloxamer 124, poloxamer 237, or poloxamer 338. In some embodiments, the copolymer comprises poloxamer 407. In certain embodiments, the polymer or copolymer comprises a phosphate ester monomer. In certain embodiments, the copolymer comprises a poloxamer and a phosphate ester monomer.
Other exemplary polymers suitable for use in the polymer or copolymer include aliphatic polyesters such as poly (lactic acid), poly (glycolic acid), and poly (lactic-co-glycolic acid); poly (trimethylene carbonate); polydioxanones and copolymers; poly (butylene succinate) (e.g. polybutylene succinate/adipate copolymer, to
Figure BDA0001614314770000201
Sold as Showa Highpolymer co.ltd.) and poly (butylene adipate); polyanhydrides such as poly (adipic anhydride) and poly (sebacic acid-co-1, 3-bis (p-carboxyphenoxy) propane; poly (ortho esters); poly (ester amides), such as polymers based on 1, 4-butanediol, adipic acid and 1, 6-aminocaproic acid (BAK1095, Bayer AG, levikusen); poly (ester urethane); poly (ester anhydrides); poly (ester carbonates), such as tyrosine-poly (alkylene oxide) -derived poly (ether carbonates); polyphosphazenes, polyacrylates such as tyrosine derived polyacrylates; poly (ether esters), e.g. poly (butylene terephthalate) -poly (ethylene glycol) copolymers
Figure BDA0001614314770000202
Poly (epsilon-caprolactone) -poly (ethylene glycol)) block copolymers and poly (ethylene oxide) -poly (hydroxybutyrate) block copolymers; polypropylfumarate; a polyacetal; a polyether; biodegradable polycyanoacrylates; biodegradable polyurethanes; polyphosphate ester; poly (amide-enamines); a polyamide; poly (amino acids); polycaprolactone; and polyhydroxyalkanoates.
In certain embodiments, the polymer or copolymer comprises poly (lactic acid) (PLA), poly (glycolic acid) (PGA), a copolymer of PLA and PGA (e.g., poly (lactide-co-glycolide) (PLG)), poly (caprolactone) (PCL), poly (lactide-co-caprolactone) (PLC), or poly (glycolide-co-caprolactone) (PGC).
In certain embodiments, the copolymer is a block copolymer of the formula a-B-a, wherein B is a hydrophobic block and each a is a non-hydrophobic block. In certain embodiments, the copolymer is a block copolymer of the formula C-A-B-A-C, wherein each B or C is a hydrophobic block, and A is a non-hydrophobic block. The polymers A-B-A and C-A-B-A-C may also comprise end groups attached to the end blocks A or C. In certain embodiments, B and C are different polymers. In certain embodiments, B and C are the same polymer. In certain embodiments, each block a is a polymer of 1 to 400 monomers. In certain embodiments, block a is a polymer of 20 to 200 monomers. In certain embodiments, each block B is a polymer of 1 to 400 monomers. In certain embodiments, block B is a polymer of 20 to 200 monomers. In certain embodiments, each block C is a polymer of 1 to 400 monomers. In certain embodiments, block C is a polymer of 20 to 200 monomers. In certain embodiments, each block a comprises a single type of monomer. In certain embodiments, each block a comprises more than one type of monomer. In certain embodiments, each block B comprises a single type of monomer. In certain embodiments, each block B comprises more than one type of monomer. In certain embodiments, each block C comprises a single type of monomer. In certain embodiments, each block C comprises more than one type of monomer.
In certain embodiments, polymer a is a hydrophilic polyether (e.g., polyethylene oxide). In certain embodiments, polymer a is a hydrophilic polyester (e.g., polyglycolic acid). In certain embodiments, polymer B is a hydrophobic polyether (e.g., polypropylene oxide). In certain embodiments, polymer B is a hydrophobic polyester (e.g., polylactic acid). In certain embodiments, polymer B is a hydrophobic polyether (e.g., polypropylene oxide). In certain embodiments, polymer B is a hydrophobic polyester (e.g., polylactic acid). In certain embodiments, polymer C is a polyphosphate.
The composition may be a liquid prior to warming above the phase transition temperature. In some embodiments, the phase transition temperature is at or below the body temperature of the subject (e.g., about 37 ℃). Thus, the composition may form a gel upon administration to a subject, for example, when the composition contacts a biological surface. In some embodiments, the phase transition temperature is from about 0 ℃ to about 37 ℃, from about 10 ℃ to about 37 ℃, from about 15 ℃ to about 37 ℃, from about 20 ℃ to about 37 ℃, from about 25 ℃ to about 37 ℃, from about 30 ℃ to about 35 ℃, or from about 35 ℃ to about 40 ℃. In some embodiments, the phase transition temperature is from about 20 ℃ to about 37 ℃. In some embodiments, the phase transition temperature is from about 0 ℃ to about 60 ℃, from about 10 ℃ to about 50 ℃, from about 20 ℃ to about 40 ℃, or from about 25 ℃ to about 35 ℃. In some embodiments, the phase transition temperature is from about 20 ℃ to 25 ℃, from about 25 ℃ to about 30 ℃, from about 30 ℃ to about 35 ℃, or from about 35 ℃ to about 40 ℃. In some embodiments, the phase transition temperature is from about 10 ℃ to about 50 ℃. In some embodiments, the phase transition temperature is from about 20 ℃ to about 40 ℃. In some embodiments, the phase transition temperature is from about 15 ℃ to about 40 ℃.
For any composition comprising a matrix forming agent, the phase transition temperature of the composition may change if additives are added to the composition. The phase transition temperature of the composition with the additive may be higher, lower or the same, depending on the characteristics of the composition and the additive, relative to a reference composition without the additive. The term reference composition as used herein refers to a composition that contains the same components as the composition to which it is being compared, except for the specified components (e.g., penetration enhancer). Unless otherwise specified, the difference in% weight/volume with or without penetration enhancer consists of a change in% weight/volume of solvent (e.g., water). In certain embodiments, the reference composition comprises the therapeutic agent and the matrix forming agent, but does not comprise a penetration enhancer. In certain embodiments, the reference composition comprises a matrix forming agent, but does not comprise a therapeutic agent or a penetration enhancer. In certain embodiments, the reference composition comprises a penetration enhancer and a matrix forming agent, but does not comprise a therapeutic agent.
In certain embodiments, the phase transition temperature of the composition is greater than the phase transition temperature of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature plus about 5 ℃, 4 ℃, about 3 ℃, about 2 ℃, or about 1 ℃ of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of the reference composition (e.g., the composition without the permeation enhancer) plus about 5 ℃. In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of the reference composition (e.g., the composition without the permeation enhancer) plus about 37 ℃. In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature plus about 30 ℃, about 20 ℃, or about 10 ℃ of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the phase transition temperature of the composition is lower than the phase transition temperature of a reference composition (e.g., a composition without a permeation enhancer).
In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of a reference composition (e.g., a composition without a permeation enhancer) plus about 5 ℃, plus about 2 ℃, or plus about 1 ℃, and greater than about 0 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, or about 30 ℃. In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of the reference composition (e.g., the composition without the permeation enhancer) plus about 5 ℃ and greater than about 20 ℃.
As one non-limiting example, consider the following composition. The phase transition temperature of composition "A" comprising about 33 ℃: (i) 1% ciprofloxacin and (ii) 18% poloxamer 407/polybutylphosphate copolymer. For the corresponding composition "B" comprising the component of "a" and (iii) 1% sodium lauryl sulfate, the phase transition temperature was reduced to about 31 ℃. For the corresponding composition "C" comprising the component of "a" and (iii) 0.5% bupivacaine, the phase transition temperature was maintained at about 33 ℃. Compositions "B" and "C" both meet the following criteria: the phase transition temperature of the composition with the permeation enhancer is lower or slightly higher (e.g., < 5 ℃) than the phase transition temperature of the composition without the permeation enhancer.
In certain embodiments, the composition is a gel at a temperature above the phase transition temperature and below about 60 ℃, below about 50 ℃, or below about 40 ℃. In certain embodiments, the composition is a gel at a temperature above the phase transition temperature and below about 50 ℃. In certain embodiments, the composition is a gel at a temperature of from about 0 ℃ to about 60 ℃, from about 10 ℃ to about 50 ℃, from about 20 ℃ to about 40 ℃, or from about 25 ℃ to about 35 ℃. In some embodiments, the composition is a gel at a temperature of about 20 ℃ to 25 ℃, about 25 ℃ to about 30 ℃, about 30 ℃ to about 35 ℃, or about 35 ℃ to about 40 ℃. In some embodiments, the composition is a gel at a temperature of about 10 ℃ to about 50 ℃. In some embodiments, the composition is a gel at a temperature of about 20 ℃ to about 40 ℃. In some embodiments, the composition is a gel at a temperature of about 15 ℃ to about 40 ℃.
For any composition comprising a matrix former, the storage modulus and loss modulus of the composition may vary if additives are added to the composition. The storage modulus of a composition with an additive may be higher, lower, or the same, depending on the characteristics of the composition and the additive, relative to the same composition without the additive. The loss modulus of the composition with the additive may be higher, lower or the same, depending on the characteristics of the composition and the additive, relative to the reference composition without the additive. In certain embodiments, the reference composition comprises the therapeutic agent and the matrix-forming agent, but does not comprise a penetration enhancer. In certain embodiments, the reference composition comprises a matrix-forming agent, but does not comprise a therapeutic agent or a penetration enhancer. In certain embodiments, the reference composition comprises a penetration enhancer and a matrix forming agent, but does not comprise a therapeutic agent.
In certain embodiments, condition (ii) is satisfied, i.e., the storage modulus of the composition is greater than about 15%, or greater than about 500Pa, whichever is less, of the storage modulus of the reference composition. In certain embodiments, condition (ii) is satisfied, i.e., the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition, or greater than about 1000Pa, whichever is less. In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 15%, greater than about 30%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 100% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 15% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 30% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 50% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 70% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 80% or about 90% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 100% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 175%, or greater than about 200% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the storage modulus of the composition at a given temperature is less than about 200%, less than about 500%, or less than about 1000% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the given temperature is about 37 ℃. In certain embodiments, the given temperature is a temperature of from the phase transition temperature to about 37 ℃.
In certain embodiments, the loss modulus of the composition is less than about 200%, less than about 150%, less than about 125%, less than about 110%, or less than about 100% of the storage modulus of a reference composition (e.g., a composition without a permeation enhancer) at a given temperature. In certain embodiments, the loss modulus of the composition at a given temperature is greater than about 50%, less than about 75%, or greater than about 90% of the loss modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the composition has a loss modulus at a given temperature that is from about 50% to about 150%, from about 70% to about 130%, from about 80% to about 120%, or from about 90% to about 110% of the loss modulus of a reference composition (e.g., a composition without a permeation enhancer). In certain embodiments, the composition has a loss modulus of about 80% to about 120% of the loss modulus of a reference composition (e.g., a composition without a permeation enhancer) at a given temperature. In certain embodiments, condition (iii): the loss modulus of the composition is about 15% to about 150% of the loss modulus of the reference composition at a temperature of about 37 ℃. In certain embodiments, the given temperature is about 37 ℃. In certain embodiments, the given temperature is a temperature from the phase transition temperature to about 37 ℃.
In certain embodiments, the composition comprises at least about 0.1% penetration enhancer. In certain embodiments, the composition comprises at least about 0.5% penetration enhancer. In certain embodiments, the composition comprises at least about 1% penetration enhancer. In certain embodiments, the composition comprises at least about 2% penetration enhancer. In certain embodiments, the composition comprises at least about 3% penetration enhancer. In certain embodiments, the composition comprises at least about 4% penetration enhancer. In certain embodiments, the composition comprises at least about 5% penetration enhancer. In certain embodiments, the composition comprises at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% penetration enhancer. In certain embodiments, the composition comprises at least about 0.5% weight/volume of the composition (w/v) of a permeation enhancer. In certain embodiments, the composition comprises at least about 1% weight/volume penetration enhancer. In certain embodiments, the composition comprises at least about 2% weight/volume penetration enhancer. In certain embodiments, the composition comprises at least about 3% weight/volume penetration enhancer. In certain embodiments, the composition comprises at least about 4% weight/volume penetration enhancer. In certain embodiments, the composition comprises at least about 5% penetration enhancer. In certain embodiments, the composition comprises at least about 6% weight/volume penetration enhancer. In certain embodiments, the composition comprises at least about 7% weight/volume penetration enhancer. In certain embodiments, the composition comprises at least about 8% weight/volume penetration enhancer. In certain embodiments, the composition comprises from about 0.1% to about 1% of a penetration enhancer. In certain embodiments, the composition comprises from about 0.5% to about 3% of a penetration enhancer. In certain embodiments, the composition comprises from about 0.5% to about 10% of a penetration enhancer. In certain embodiments, the composition comprises from about 2% to about 10% of a penetration enhancer.
In certain embodiments, the composition is applied to a surface having a temperature at or above the phase transition temperature. In some embodiments, the surface is a biological surface. In certain embodiments, the surface is skin. In certain embodiments, the surface is a surface in the ear canal of the subject. In certain embodiments, the subject is the tympanic membrane. In certain embodiments, the surface is a surface in the respiratory tract (e.g., in the nasal or buccal cavity) of the subject. In certain embodiments, the surface is a surface in the mouth of the subject (e.g., a surface of a tooth or gum). The composition may be applied to an internal body surface, for example, by intradermal or intradermal delivery or during a surgical procedure. In certain embodiments, the surface is an intradermal surface. In certain embodiments, the surface is a surface of an organ (e.g., heart, lung, spleen, pancreas, kidney, liver, stomach, intestine, bladder). In certain embodiments, the surface is connective tissue. In certain embodiments, the surface is muscle tissue (e.g., smooth muscle, skeletal muscle, cardiac muscle). In certain embodiments, the surface is a neural tissue (e.g., brain, spinal cord). In certain embodiments, the surface is epithelial tissue. In certain embodiments, the surface is a surface of the alimentary canal (e.g., colon, rectum). In certain embodiments, the surface is epithelial tissue. In certain embodiments, the surface is a surface of the reproductive tract (e.g., vagina, cervix). In certain embodiments, the surface is bone. In certain embodiments, the surface is vascular tissue. In certain embodiments, the surface is a wound bed (wound bed). In certain embodiments, the surface is a biofilm. In certain embodiments, the surface is hair or fur. In certain embodiments, the surface is a surface of a medical implant.
In general, for the addition of penetration enhancers, small or no changes in phase transition temperature, storage modulus, or loss modulus are preferred. A small change is considered to be a change in phase transition temperature of less than 5 c, or a change in modulus of less than 10%. For changes in phase transition temperature, lower phase transition temperatures of compositions with permeation enhancers are preferred. The shift to the lower phase transition temperature, as opposed to the "right shift" or "R shift," may be referred to as a "left shift" or "L shift. For the change in storage modulus, a higher storage modulus for the composition with the permeation enhancer is preferred. For the change in loss modulus, a lower loss modulus for the composition with the permeation enhancer is preferred.
In certain embodiments, the phase transition temperature of the composition is within about 5 ℃, within about 3 ℃, or within about 1 ℃ of the phase transition temperature of the reference composition, wherein the composition comprises the penetration enhancer P1 and the reference composition does not comprise the penetration enhancer P1. In certain embodiments, the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of a reference composition, wherein the composition comprises the permeation enhancer P1 and the reference composition does not comprise the permeation enhancer P1. In certain embodiments, the composition has a loss modulus within about 10%, within about 5%, or within about 2% of the loss modulus of a reference composition, wherein the composition comprises penetration enhancer P1 and the reference composition does not comprise penetration enhancer P1. In certain embodiments, the phase transition temperature of the composition is within about 5 ℃, within about 3 ℃, or within about 1 ℃ of the phase transition temperature of the reference composition and the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of the reference composition, wherein the composition comprises the penetration enhancer P1 and the reference composition does not comprise the penetration enhancer P1.
In certain embodiments, the penetration enhancer P1 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, aminoamide, aminoester, azide-containing compound, or alcohol. In certain embodiments, the penetration enhancer P1 is a surfactant (anionic, cationic, nonionic)Daughter, zwitterionic), terpenes, anesthetics, aminoamides, amino esters, azide-containing compounds, pyrrolidones, sulfoxides, fatty acids, or alcohols. In certain embodiments, the penetration enhancer P1 is a surfactant (e.g., sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethylammonium bromide, cetyl pyridinium chloride
Figure BDA0001614314770000261
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl chembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure BDA0001614314770000262
Chlorinated dodecyl pyridine
Figure BDA0001614314770000263
Cetyl pyridinium chloride
Figure BDA0001614314770000264
Benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80). In certain embodiments, the penetration enhancer P1 is a terpene (e.g., limonene, cymene, pinene, camphor, menthol, phosphone, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, β -caryophyllene, eucalyptol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and palmitic acid)Linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, ethylpiperazine carboxylate). In certain embodiments, the penetration enhancer P1 is a terpene. In certain embodiments, the composition comprises from 0.5% to 6.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of terpene. In certain embodiments, the composition comprises 2.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight limonene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight limonene. In certain embodiments, the composition comprises 2.0% by weight of limonene. In certain embodiments, the penetration enhancer P1 is an anesthetic (e.g., bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomethicaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, perocaine, trimethacaine). In some embodiments, the penetration enhancer P1 is bupivacaine. In some embodiments, the permeation enhancer P1 is sodium lauryl sulfate. In some embodiments, the penetration enhancer P1 is limonene. In some embodiments, the penetration enhancer P1 is a combination of at least two of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer P1 is a combination of bupivacaine, sodium lauryl sulfate, and limonene. In certain embodiments, the penetration enhancer P1 is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000MW), or octyldodecanol.
In certain embodiments, the phase transition temperature of the composition is lower than the phase transition temperature of a reference composition, wherein the composition comprises penetration enhancer P2 and the reference composition does not comprise penetration enhancer P2. In certain embodiments, the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of a reference composition, wherein the composition comprises the permeation enhancer P2 and the reference composition does not comprise the permeation enhancer P2. In certain embodiments, the storage modulus of the composition is within about 100%, within about 10%, within about 5%, or within about 2% of the storage modulus of a reference composition, wherein the composition comprises the permeation enhancer P2 and the reference composition does not comprise the permeation enhancer P2. In certain embodiments, the composition has a loss modulus within about 10%, within about 5%, or within about 2% of the loss modulus of a reference composition, wherein the composition comprises penetration enhancer P2 and the reference composition does not comprise penetration enhancer P2. In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of the reference composition and the storage modulus of the composition is within about 10%, within about 5%, or within about 2% of the storage modulus of the reference composition, wherein the composition comprises the permeation enhancer P2 and the reference composition does not comprise the permeation enhancer P2.
In certain embodiments, the penetration enhancer P2 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, aminoamide, aminoester, azide-containing compound, or alcohol. In certain embodiments, the penetration enhancer P2 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, amino amide, amino ester, azide-containing compound, pyrrolidone, sulfoxide, fatty acid, or alcohol. In certain embodiments, the penetration enhancer P2 is a surfactant (e.g., sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethylammonium bromide, cetyl pyridinium chloride
Figure BDA0001614314770000271
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate,Oleylchembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure BDA0001614314770000272
Chlorinated dodecyl pyridine
Figure BDA0001614314770000273
Cetyl pyridinium chloride
Figure BDA0001614314770000274
Benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80). In certain embodiments, the penetration enhancer P2 is a terpene (e.g., limonene, cymene, pinene, camphor, menthol, comphone, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupene, β -caryophyllene, eucalyptol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid, ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, ethylpiperazine carboxylate). In certain embodiments, the penetration enhancer P2 is a terpene. In certain embodiments, the composition comprises from 0.5% to 6.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of terpene. In certain embodiments, the composition comprises 2.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight limonene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight limonene. In certain embodiments The composition comprises 2.0% by weight of limonene. In certain embodiments, the penetration enhancer P2 is an anesthetic (e.g., bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomethiocaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, perocaine, trimetaine). In some embodiments, the penetration enhancer P2 is bupivacaine. In some embodiments, the permeation enhancer P2 is sodium lauryl sulfate. In some embodiments, the penetration enhancer P2 is limonene. In some embodiments, the penetration enhancer P2 is a combination of at least two of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer P2 is a combination of bupivacaine, sodium lauryl sulfate, and limonene. In certain embodiments, the penetration enhancer P2 is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000MW), or octyldodecanol.
In certain embodiments, the phase transition temperature of the composition is lower than the phase transition temperature of a reference composition, wherein the composition comprises penetration enhancer P3 and the reference composition does not comprise penetration enhancer P3. In certain embodiments, the storage modulus of the composition is greater than the storage modulus of a reference composition, wherein the composition comprises the permeation enhancer P3 and the reference composition does not comprise the permeation enhancer P3. In certain embodiments, the composition has a loss modulus greater than the loss modulus of a reference composition, wherein the composition comprises penetration enhancer P3 and the reference composition does not comprise penetration enhancer P3. In certain embodiments, the phase transition temperature of the composition is less than the phase transition temperature of the reference composition and the storage modulus of the composition is greater than the storage modulus of the reference composition, wherein the composition comprises the penetration enhancer P3 and the reference composition does not comprise the penetration enhancer P3.
In certain embodiments, the penetration enhancer P3 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, aminoamide, aminoesterAn azide-containing compound, or an alcohol. In certain embodiments, the penetration enhancer P3 is a surfactant (anionic, cationic, nonionic, zwitterionic), terpene, anesthetic, aminoamide, aminoester, azide-containing compound, pyrrolidone, sulfoxide, fatty acid, or alcohol. In certain embodiments, the penetration enhancer P3 is a surfactant (e.g., sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethylammonium bromide, cetyl pyridinium chloride
Figure BDA0001614314770000291
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl chembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure BDA0001614314770000292
Chlorinated dodecyl pyridine
Figure BDA0001614314770000293
Cetyl pyridinium chloride
Figure BDA0001614314770000294
Benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80). In certain embodiments, the penetration enhancer P3 is a terpene (e.g., limonene, cymene, pinene, camphor, menthol, comphone, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, β -caryophyllene, eucalyptolCaproic acid, caprylic acid, capric acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, ethylpiperazine carboxylate). In certain embodiments, the penetration enhancer P3 is a terpene. In certain embodiments, the composition comprises from 0.5% to 6.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight of terpene. In certain embodiments, the composition comprises 2.0% by weight of terpene. In certain embodiments, the composition comprises 1.5% to 3.0% by weight limonene. In certain embodiments, the composition comprises 1.5% to 2.0% by weight limonene. In certain embodiments, the composition comprises 2.0% by weight of limonene. In certain embodiments, the penetration enhancer P3 is an anesthetic (e.g., bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomethiocaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, perocaine, trimetaine). In some embodiments, the penetration enhancer P3 is bupivacaine. In some embodiments, the permeation enhancer P3 is sodium lauryl sulfate. In some embodiments, the penetration enhancer P3 is limonene. In some embodiments, the penetration enhancer P3 is a combination of at least two of a surfactant, a terpene, and an anesthetic. In some embodiments, the penetration enhancer P3 is a combination of bupivacaine, sodium lauryl sulfate, and limonene. In certain embodiments, the penetration enhancer P3 is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (2500000MW), or octyldodecanol.
In certain embodiments, the compositions are useful for treating diseases. In some embodiments, the composition can be used to treat an infectious disease. In some embodiments, the composition can be used to treat an otic disorder (e.g., the barrier is the tympanic membrane). In some embodiments, the composition can be used to treat otitis media.
As described, the gelling temperature (phase transition temperature) of the composition is one factor in determining whether the composition is suitable (e.g., allows for sustained delivery to the tympanic membrane). The temperature at which the storage modulus exceeds the loss modulus is considered the gelling temperature. The gelling temperature of the compositions herein may be below or above 37 ℃, but is preferably below 37 ℃ to accelerate gelling of the composition, particularly the matrix forming agent, upon exposure to body heat immediately after application.
The timing of the sol-gel transition will affect the ease of application. In general, a faster in situ transition is useful for administration to a subject (e.g., a child resistant to compliance). In certain embodiments, the composition gels within about 5 seconds, about 10 seconds, about 20 seconds, about 30 seconds, about 1 minute, about 5 minutes, or about 10 minutes of administration (e.g., to the ear canal). In some embodiments, the composition gels from about 1 second to about 20 seconds after application.
In certain embodiments, the composition is cold stored (e.g., refrigerated at about 5 ℃) prior to application. Cold storage may be useful for compositions with gelling temperatures below room temperature to prevent gelling prior to application or during handling.
In one aspect, provided herein is a composition comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a block copolymer comprising a hydrophobic monomer (e.g., a phosphate ester monomer);
wherein:
the composition forms a gel at a temperature above the phase transition temperature; and a phase transition temperature of less than about 37 ℃;
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) at a temperature of about 37 ℃, the storage modulus of the composition is greater than about 70% of the storage modulus of the reference composition; and
(iii) the composition has a loss modulus of from about 80% to about 120% of the loss modulus of the reference composition at a temperature of about 37 ℃;
Wherein the reference composition is the composition in the absence of a penetration enhancer or a combination of penetration enhancers.
In one aspect, provided herein is a composition comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a block copolymer comprising a hydrophobic monomer (e.g., a phosphate ester monomer);
wherein:
the composition forms a gel at a temperature above the phase transition temperature; and a phase transition temperature of less than about 37 ℃:
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) a storage modulus of the composition at a temperature of about 37 ℃ that is greater than about 15% or greater than about 500Pa, whichever is less, of a storage modulus of a reference composition; and
(iii) the composition has a loss modulus of from about 15% to about 150% of the loss modulus of the reference composition at a temperature of about 37 ℃;
Wherein the reference composition is the composition in the absence of a penetration enhancer or a combination of penetration enhancers.
In another aspect, provided herein is a composition for treating an infectious disease, comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a copolymer comprising a phosphate ester monomer.
In another aspect, provided herein is a composition for treating an otic disorder, comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the tympanic membrane; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a copolymer comprising a phosphate ester monomer.
In another aspect, provided herein is a composition comprising:
(a) A diagnostic agent or combination of diagnostic agents;
(b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the tympanic membrane; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a copolymer comprising a phosphate ester monomer.
In another aspect, provided herein is a composition for treating an infectious disease, comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a permeation enhancer or combination of permeation enhancers, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the barrier; and
(c) a matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent comprises a polysaccharide derivative comprising crosslinkable functional groups.
In another aspect, provided herein is a composition for treating an otic disorder, comprising:
(a) a therapeutic agent or combination of therapeutic agents;
(b) a penetration enhancer or a combination of penetration enhancers, wherein the penetration enhancer or combination of penetration enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across the tympanic membrane; and
(c) A matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent comprises a polysaccharide derivative comprising crosslinkable functional groups.
The compositions provided herein generally comprise a penetration enhancer (e.g., surfactant, terpene), a therapeutic agent (e.g., antibiotic), and a matrix forming agent (e.g., poloxamer derivatives, polyphosphate-containing polymers, polysaccharide derivatives). Permeation enhancers are agents that alter the stratum corneum of the tympanic membrane to increase the flux of a therapeutic agent across the tympanic membrane. The permeation enhancer aids in the delivery of the therapeutic agent into the middle and/or inner ear. Therapeutic agents include agents that have therapeutic benefit in the ear. In certain embodiments, the matrix forming agent is a liquid at ambient conditions that gels (e.g., becomes more viscous) upon administration to a subject. In certain embodiments, the matrix forming agent gels after mixing the two components of the composition. In some embodiments, each component comprises a matrix forming agent (e.g., two polysaccharide derivatives that are cross-linked after mixing). In some embodiments, one component comprises a matrix former and the second component comprises an activator or catalyst that causes gelling when mixed with the matrix former. In certain embodiments, the pharmaceutical composition does not substantially interfere with the hearing of the subject.
Matrix forming agent
A matrix forming agent is a compound or mixture of compounds that forms a gel after application. In certain embodiments, the matrix forming agent forms a gel upon administration into the ear canal of a subject. The gel composition serves as a reservoir containing the therapeutic agent and the permeation enhancer, thereby allowing for sustained release of the therapeutic agent across a barrier (e.g., the tympanic membrane). In certain embodiments, the gel maintains contact with the tympanic membrane. In some embodiments, the gel is maintained in contact for 0.5 to 1 hour, 1 to 4 hours, 1 to 8 hours, 1 to 16 hours, or 1 to 24 hours. In some embodiments, the gel is maintained in contact for 1 to 3 days, 1 to 7 days, or 1 to 14 days. In some embodiments, the gel allows flux of the therapeutic agent across the tympanic membrane for 0.5 to 1 hour, 1 to 4 hours, 1 to 8 hours, 1 to 16 hours, or 1 to 24 hours. In some embodiments, the gel is maintained in contact for 1 to 3 days, 1 to 7 days, or 1 to 14 days. Such reservoirs maintain contact with the tympanic membrane, thereby increasing the time that the therapeutic agent passes through the tympanic membrane and is delivered to the middle or inner ear. Such reservoirs maximize exposure of the tympanic membrane to the permeation enhancer and therapeutic agent and facilitate sustained flux of the therapeutic agent into the middle and inner ear.
In various embodiments, the composition is a sustained release formulation. In various aspects, the sustained release of the permeation enhancer and/or therapeutic agent can be at a constant rate to deliver an effective amount of the permeation enhancer or therapeutic agent to the surface of the tympanic membrane, middle ear, or inner ear. In various embodiments, sustained release provides sufficient therapeutic agent flux over about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In various embodiments, sustained release provides sufficient therapeutic agent flux over about 7 to about 10 days. In various embodiments, the sustained release may be at a constant rate for about 7 days to about 14 days. In various embodiments, sustained release provides sufficient therapeutic agent flux over about 14 to about 21 days. In various embodiments, sustained release provides sufficient therapeutic agent flux over about 21 to about 30 days. As used herein, sufficient flux is the flux required for the therapeutic agent to be present in the middle ear in a therapeutically effective amount or a prophylactically effective amount. In some embodiments, sufficient flux is sufficient to provide an antibiotic agent at a concentration equal to or greater than the minimum inhibitory concentration for the infectious microbe. In some embodiments, the infectious microorganism is haemophilus influenzae, streptococcus pneumoniae, or moraxella catarrhalis.
In various aspects, a sustained release profile is obtained by adding a matrix forming agent to the composition. In various embodiments, the composition may further comprise a matrix forming agent. In various embodiments, the matrix forming agent may undergo an in situ viscosity change based on a phase change, a solubility change, solvent evaporation, or mixing of components comprising the matrix forming agent. Such matrix-forming agents gel in situ after administration into the ear canal of a patient to form a reservoir containing the therapeutic agent and the permeation enhancer, thereby allowing for sustained release of the therapeutic agent. Such reservoirs maintain contact with the tympanic membrane, thereby increasing the time for the therapeutic agent to permeate the tympanic membrane and be delivered to the middle or inner ear. Such a reservoir maximizes exposure of the tympanic membrane to the permeation enhancer and therapeutic agent.
In certain embodiments, the matrix-forming agent is a hydrogel, or forms a hydrogel after administration. Matrix-forming agents may include, but are not limited to, polyelectrolyte complexes, thermally responsive gelling agents, prepolymers, alginates, uncrosslinked polymers, and monomers, thermally responsive gelling agents (e.g., poloxamer-polyphosphate copolymers), and polymers having crosslinkable functional groups. In certain embodiments, the matrix forming agent is separated into first and second components that form a matrix or gel upon mixing. In some embodiments, the first matrix-former component is a first polymer comprising a first type of crosslinkable functional group and the second matrix-former component is a second polymer comprising a second type of crosslinkable functional group, wherein upon mixing the first and second components, both types of crosslinkable functional groups form crosslinks between the two polymers. In some embodiments, the first matrix-former component comprises a polymer having crosslinkable functional groups and the second matrix-former component comprises an activator, wherein the crosslinkable functional groups form crosslinks between the polymers after mixing the first and second components. In some embodiments, the activator is an acid, a base, or a catalyst.
The matrix forming agent may also comprise a biocompatible agent. The matrix forming agent may also comprise a biodegradable agent. In certain embodiments, the matrix forming agent degrades and is excreted from the patient within 3 days of application, within 7 days of application, within 10 days of application, or within 14 days of application. In various embodiments, the matrixing agent has little or no effect on hearing threshold when applied to the ear canal of a subject. In various aspects, the matrix forming agent can comprise from about 0 to about 40% of the composition. In various embodiments, the matrix forming agent may comprise from about 0 to about 10% of the composition, from about 10% to about 20% of the composition, from about 20% to about 30% of the composition, from about 30% to about 40% of the composition, or from about 40% to about 50% of the composition.
The polymer may be a block copolymer. Exemplary polymer types suitable for use in the block copolymer include, but are not limited to: a polyethylene oxide/polypropylene oxide based system, poloxamer 407, poloxamer 188, poloxamine, methylcellulose, hydroxypropylmethylcellulose, ethyl (hydroxyethyl) cellulose, xyloglucan, cellulose, acetate phthalate, latex, poly (acrylic acid), heat responsive polysaccharides including cellulose derivatives, chitosan, dextran and gellan gum. In some embodiments, the matrix forming agent comprises a polyethylene/polypropylene copolymer or a polyethylene/polypropylene block copolymer. In some embodiments, the matrix forming agent comprises a poloxamer. In some embodiments, the matrix forming agent comprises poloxamer 407, poloxamer 188, poloxamine, poloxamer 124, poloxamer 237 or poloxamer 338.
Exemplary poloxamers include, but are not limited to: poloxamer 407, poloxamer 188, poloxamine, poloxamer 124, poloxamer 237, or poloxamer 338,
Figure BDA0001614314770000351
10R5、
Figure BDA0001614314770000352
17R2、
Figure BDA0001614314770000353
17R4、
Figure BDA0001614314770000354
25R2、
Figure BDA0001614314770000355
25R4、
Figure BDA0001614314770000356
31R1、
Figure BDA0001614314770000357
F108 casting Solid Surfactant (Cast Solid Surfactant),
Figure BDA0001614314770000358
F 108 NF、
Figure BDA0001614314770000359
F 108 Pastille、
Figure BDA00016143147700003510
F108 NF Prill poloxamer 338,
Figure BDA00016143147700003511
F 127 NF、
Figure BDA00016143147700003512
F 127 NF 500 BHT Prill、
Figure BDA00016143147700003513
F127 NF Prill poloxamer 407,
Figure BDA00016143147700003514
F 38、
Figure BDA00016143147700003515
F 38 Pastille、
Figure BDA00016143147700003516
F 68、
Figure BDA00016143147700003517
F 68 LF Pastille、
Figure BDA00016143147700003518
F 68 NF、
Figure BDA00016143147700003519
F68 NF Prill poloxamer 188,
Figure BDA00016143147700003520
F 68 Pastille、
Figure BDA00016143147700003521
F 77、
Figure BDA00016143147700003522
F 77 Micropastille、
Figure BDA00016143147700003523
F 87、
Figure BDA00016143147700003524
F 87 NF、
Figure BDA00016143147700003525
F87 NF Prill poloxamer 237,
Figure BDA00016143147700003526
F 88、
Figure BDA00016143147700003527
F 88 Pastille、
Figure BDA00016143147700003528
FT L 61、
Figure BDA00016143147700003529
L 10、
Figure BDA00016143147700003530
L 101、
Figure BDA00016143147700003531
L 121、
Figure BDA00016143147700003532
L 31、
Figure BDA00016143147700003533
L 35、
Figure BDA00016143147700003534
L 43、
Figure BDA00016143147700003535
L 61、
Figure BDA00016143147700003536
L 62、
Figure BDA00016143147700003537
L 62 LF、
Figure BDA00016143147700003538
L 62D、
Figure BDA00016143147700003539
L 64、
Figure BDA00016143147700003540
L 81、
Figure BDA00016143147700003541
L 92、
Figure BDA00016143147700003542
L44 NF INH surfactant poloxamer 124,
Figure BDA00016143147700003543
N 3、
Figure BDA00016143147700003544
P 103、
Figure BDA00016143147700003545
P 104、
Figure BDA00016143147700003546
P 105、
Figure BDA00016143147700003547
P123 surfactant,
Figure BDA00016143147700003548
P 65、
Figure BDA00016143147700003549
P 84、
Figure BDA00016143147700003550
P 85、
Figure BDA00016143147700003551
PE/F 108、
Figure BDA00016143147700003552
PE/P105、
Figure BDA00016143147700003553
PE/P84、
Figure BDA00016143147700003554
PE/L31、
Figure BDA00016143147700003555
PE/L61、
Figure BDA00016143147700003556
PE/L101、
Figure BDA00016143147700003557
PE/L121、
Figure BDA00016143147700003558
PE/L42、
Figure BDA00016143147700003559
PE/L62、
Figure BDA00016143147700003560
PE/L92、
Figure BDA00016143147700003561
PE/L44、
Figure BDA00016143147700003562
PE/L64、
Figure BDA00016143147700003563
PE/P84、
Figure BDA00016143147700003564
PE/P75、
Figure BDA00016143147700003565
PE/P103、
Figure BDA00016143147700003566
PE/F87、
Figure BDA00016143147700003567
PE/F127、
Figure BDA00016143147700003568
PE/F38、
Figure BDA00016143147700003569
PE/F68、
Figure BDA00016143147700003570
P 188、
Figure BDA00016143147700003571
P 407、
Figure BDA00016143147700003572
P 188 micro、
Figure BDA00016143147700003573
P 407 micro、
Figure BDA00016143147700003574
P237、
Figure BDA00016143147700003575
P 338、
Figure BDA00016143147700003576
EL、
Figure BDA00016143147700003577
HS 15、
Figure BDA00016143147700003578
PS 80、
Figure BDA00016143147700003579
PS 60、
Figure BDA00016143147700003580
RH 40、
Figure BDA00016143147700003581
TPG S、
Figure BDA0001614314770000361
CS L、
Figure BDA0001614314770000362
CS A、
Figure BDA0001614314770000363
CS S、
Figure BDA0001614314770000364
CS B、
Figure BDA0001614314770000365
CS 20 and
Figure BDA0001614314770000366
and (3) a CS 12. In some embodiments, the matrix forming agent comprises any of the foregoing poloxamers, derivatives thereof, or block copolymers thereof.
In various embodiments of the present invention, polyelectrolyte complexes may include, but are not limited to: chitosan-chondroitin sulfate complex, gelatin, carboxymethylcellulose, glycosaminoglycans, and poly (vinyl alcohol). In various aspects, the relative proportion of chitosan to chondroitin sulfate can be about 1: 0.09 to about 1: 1.4. In certain embodiments, the polyelectrolyte complex is a chitosan-chondroitin sulfate complex.
In certain embodiments, the percentage weight of matrix forming agent in the composition is from about 1% to about 10%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, or from about 50% to about 90%. In some embodiments, the percentage by weight of matrix forming agent in the composition is from 1% to about 10%. In some embodiments, the percentage by weight of matrix forming agent in the composition is from about 10% to about 20%. In some embodiments, the percentage by weight of matrix forming agent in the composition is from 20% to about 30%.
Polymers comprising polyphosphate monomers or blocks
In certain embodiments, the matrix formation comprises a copolymer having a phosphate ester monomer. The copolymer comprises at least one phosphate ester monomer and at least one non-phosphate ester monomer. In some embodiments, the copolymer comprises polyphosphate blocks. In some embodiments, the copolymer comprises polyphosphate blocks and non-polyphosphate blocks. In some embodiments, the block copolymer comprises a polyphosphate block and an additional block selected from the group consisting of: polyethylene oxide, polypropylene oxide, poloxamers, poloxamer 407, poloxamer 188, poloxamines, methylcellulose, hydroxypropyl methylcellulose, ethyl (hydroxyethyl) cellulose, xyloglucan, acetate, phthalate, latex, poly (acrylic acid), N-isopropylacrylamide, cellulose, chitosan, dextran, hyaluronic acid, and derivatives thereof. In some embodiments, the polymer comprises a thermo-responsive polysaccharide (e.g., cellulose derivatives, chitosan, dextran, and gellan gum). In some embodiments, the block copolymer comprises a polyphosphate block and comprises a polyethylene/polypropylene copolymer or a polyethylene/polypropylene block copolymer. In some embodiments, the block copolymer comprises a polyphosphate block, and comprises a poloxamer. In some embodiments, the composition has a high degree of hydrophobicity. In some embodiments, the block copolymer has a high degree of hydrophobicity. In some embodiments, the composition is optically clear. In some embodiments, the block copolymer comprises a polyphosphate block, and comprises poloxamer 407. In some embodiments, each block comprises 1 to 200 monomers.
In certain embodiments, the polyphosphate copolymer or polyphosphate block comprises a monomer of formula (M):
Figure BDA0001614314770000371
wherein for each monomer, Y is independently-R1or-L2R2Wherein:
R1each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2independently for each occurrence is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
R2each occurrence is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORb、-N(Rb)2Or an oxygen protecting group; and is
RbEach occurrence is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or both RbTogether with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heterocyclic ring A substituted heteroaryl ring.
In certain embodiments, the polyphosphate copolymer or polyphosphate block comprises a monomer of formula (M-i):
Figure BDA0001614314770000372
wherein R is1As defined herein.
In certain embodiments, the polyphosphate copolymer or polyphosphate block comprises a monomer of formula (M-ii):
Figure BDA0001614314770000381
wherein L is2And R2As defined herein.
In certain embodiments, the matrix former comprises polyphosphate blocks comprising monomers of formula (M-i) and polyphosphate blocks comprising monomers of formula (M-ii). In some embodiments, the matrix former comprises polyphosphate blocks comprising monomers of both formulas (M-i) and (M-ii).
In certain embodiments, the matrix forming agent is a polymer of formula (I):
Figure BDA0001614314770000382
wherein:
each occurrence of Y is independently-R1or-L2R2；
R1Each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2independently for each occurrence is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
R2each occurrence is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR b、-N(Rb)2Or an oxygen protecting group;
R3independently for each occurrence is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -ORbor-N (R)b)2；
RbEach occurrence is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or both RbTogether with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring;
G1and G2Each independently is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate, or an oxygen protecting group; and is
p, q, r, s and t are each independently integers, inclusive, from 0 to 200, where the sum of p and t is at least 1 and the sum of q, r and s is at least 1.
The phosphate ester monomers and polyphosphate blocks described herein may comprise a group Y. In certain embodiments, each Y in the copolymer is the same substituent. In certain embodiments, each Y in the copolymer is one of two specific substituents. In certain embodiments, each Y in the copolymer is one of three specific substituents. In certain embodiments, each Y in the copolymer is one of four specific substituents. In certain embodiments, each Y in the copolymer is one of five specific substituents. In certain embodiments, each Y in the copolymer is one of six specific substituents. In certain embodiments, each Y in the copolymer is one of seven or more particular substituents And (4) seed selection. In some embodiments, Y is-R1. In some embodiments, Y is-L2R2。
In certain embodiments, p is 0. In certain embodiments, p is an integer from 1 to 100, inclusive. In some embodiments, p is an integer from 10 to 100, inclusive. In some embodiments, p is an integer from 10 to 50, inclusive. In some embodiments, p is an integer from 10 to 25, inclusive. In some embodiments, p is an integer from 1 to 10, inclusive.
In certain embodiments, t is 0. In certain embodiments, t is an integer from 1 to 100, inclusive. In some embodiments, t is an integer from 10 to 100, inclusive. In some embodiments, t is an integer from 10 to 50, inclusive. In some embodiments, t is an integer from 10 to 25, inclusive. In some embodiments, t is an integer from 1 to 10, inclusive.
In certain embodiments, q is 0. In certain embodiments, q is an integer from 1 to 100, inclusive. In some embodiments, q is an integer from 10 to 100, inclusive. In some embodiments, q is an integer from 10 to 50, inclusive. In some embodiments, q is an integer from 10 to 25, inclusive. In some embodiments, q is an integer from 1 to 10, inclusive.
In certain embodiments, r is 0. In certain embodiments, r is an integer from 1 to 100, inclusive. In some embodiments, r is an integer from 10 to 100, inclusive. In some embodiments, r is an integer from 10 to 50, inclusive. In some embodiments, r is an integer from 10 to 25, inclusive. In some embodiments, r is an integer from 1 to 10, inclusive.
In certain embodiments, s is 0. In certain embodiments, s is an integer from 1 to 100. In some embodiments, s is an integer from 10 to 100, inclusive. In some embodiments, s is an integer from 10 to 50, inclusive. In some embodiments, s is an integer from 10 to 25, inclusive. In some embodiments, s is an integer from 1 to 10, inclusive. In certain embodiments, q and s are both 0. In certain embodiments, exactly one of q and s is 0.
G1And G2Are the end groups of the polymer. As generally defined herein, G1And G2Is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate, or an oxygen protecting group. In some embodiments, G 1And G2Are the same. In some embodiments, G1And G2Both are hydrogen. In some embodiments, G1And G2Is different.
In certain embodiments, G1Is hydrogen. In certain embodiments, G1Is an optionally substituted alkyl group. In certain embodiments, G1Is an optionally substituted acyl group. In certain embodiments, G1Is an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G1Is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G1Is hydrogen. In certain embodiments, G1Is an optionally substituted alkyl group. In certain embodiments, G1Is an optionally substituted acyl group. In certain embodiments, G1Is an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G1Is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G 1Is an optionally substituted aryl group, such as an optionally substituted phenyl group. In certain embodiments, G1Is unsubstituted aryl, e.g. notA substituted phenyl group. In certain embodiments, G1Is optionally substituted heteroaryl, such as optionally substituted 5-to 6-membered heteroaryl, or optionally substituted 9-to 10-membered bicyclic heteroaryl. In certain embodiments, G1Is an unsubstituted heteroaryl group, such as an unsubstituted 5-to 6-membered heteroaryl group, or an unsubstituted 9-to 10-membered bicyclic heteroaryl group.
In certain embodiments, G2Is hydrogen. In certain embodiments, G2Is an optionally substituted alkyl group. In certain embodiments, G2Is an optionally substituted acyl group. In certain embodiments, G2Is an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G2 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G2Is hydrogen. In certain embodiments, G2Is an optionally substituted alkyl group. In certain embodiments, G 2Is an optionally substituted acyl group. In certain embodiments, G2Is an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G2Is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G2Is optionally substituted aryl, such as optionally substituted phenyl. In certain embodiments, G2Is an unsubstituted aryl group, such as an unsubstituted phenyl group. In certain embodiments, G2Is optionally substituted heteroaryl, such as optionally substituted 5-to 6-membered heteroaryl, or optionally substituted 9-to 10-membered bicyclic heteroaryl. In certain embodiments, G2Is an unsubstituted heteroaryl group, such as an unsubstituted 5-to 6-membered heteroaryl group, or an unsubstituted 9-to 10-membered bicyclic heteroaryl group.
Generally, increasing PPE hydrophobicity lowers the gelation temperature and accelerates gelation kinetics. The hydrophobicity of the PE monomer can be adjusted by the choice of the pendant group Y (see, e.g., fig. 7). In certain embodiments, a greater number of hydrophobic domains will make the polymer more resistant to the effect of CPE on micelle formation than P407. The fact that P407-PPE not only can form gels through micelle formation, but also can form gels through the formation of a cross-linked network of hydrophobic PPE domains [46] may also have similar effects and create additional means to modulate phase transition behavior. It is noted that excessively hydrophobic PPE blocks can cause the polymer to aggregate in water, which may be undesirable for application.
The bioadhesion of P407 can be enhanced by conjugation of poly (acrylic acid) (PAA) or other reactive groups. In certain embodiments, the PE monomer is functionalized with carbonyl and/or acrylate groups (see, e.g., fig. 7). In certain embodiments, both the PE monomer having a hydrophobic group and the PE monomer having a bioadhesive group are incorporated into the matrix-forming agent. In some embodiments, the hydrophobic group and the bioadhesive group are incorporated into the same polymer. In some embodiments, the hydrophobic group and the bioadhesive group are incorporated into separate polymers.
R1
The phosphate ester monomer and polyphosphate ester blocks described herein may comprise R1. In certain embodiments, each R is1Are the same substituents. In certain embodiments, each R in the polymer1Is one of two specific substituents. In certain embodiments, each R in the polymer1Is one of three specific substituents. In certain embodiments, each R in the polymer1Is one of four specific substituents. In certain embodiments, each R in the polymer1Is one of five specific substituents. In certain embodiments, each R in the polymer 1Is one of six specific substituents. In certain embodiments, each R in the polymer1Is one of seven or more specific substituents.
As generally described herein, R1Each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In certain embodiments, R1Each occurrence is independently hydrogen or optionally substituted alkyl. In certain embodiments, R1Each occurrence is independently hydrogen or unsubstituted alkyl.
In certain embodiments, R1Is hydrogen. In certain embodiments, RA1Are non-hydrogen radicals.
In certain embodiments, R1Is optionally substituted alkyl, e.g. optionally substituted C1-6Alkyl, optionally substituted C1-2Alkyl, optionally substituted C2-3Alkyl, optionally substituted C3-4Alkyl, optionally substituted C4-5Alkyl or optionally substituted C5-6An alkyl group. In certain embodiments, R1Is unsubstituted alkyl, e.g. unsubstituted C1-6Alkyl, unsubstituted C1-2Alkyl, unsubstituted C2-3Alkyl, unsubstituted C3-4Alkyl, unsubstituted C4-5Alkyl or unsubstituted C5-6An alkyl group. In certain embodiments, R1Is unsubstituted C1-20An alkyl group. In certain embodiments, R 1Is unsubstituted C1-12An alkyl group. In certain embodiments, R1Is methyl. In certain embodiments, R1Is ethyl, propyl or butyl. In certain embodiments, R1Is haloalkyl, e.g., -CHF2、-CHCl2、-CH2CHF2、-CH2CHCl2. In certain embodiments, R1Is perhaloalkyl, e.g., -CF3、-CF2CF3、-CCl3. In certain embodiments, R1Is hydroxyalkyl, e.g., -CH2OH、-CH2CH2OH、-CH2ORb、-CH2CH2ORb. In certain embodiments, R1Is aminoalkyl, e.g., -CH2NH2、-CH2CH2NH2、-CH2NMe2、-CH2CH2NMe2、-CH2N(Rb)2、-CH2CH2N(Rb)2。
In certain embodiments, R1Is optionally substituted alkenyl, e.g. optionally substituted C2-6An alkenyl group. In certain embodiments, R1Being unsubstituted alkenyl, e.g. unsubstituted C2-6An alkenyl group. In certain embodiments, R1Vinyl, allyl or isoprenyl (prenyl). In certain embodiments, R1Is optionally substituted alkynyl, e.g. optionally substituted C2-6Alkynyl. In certain embodiments, R1Is unsubstituted alkynyl, e.g. unsubstituted C2-6Alkynyl.
In certain embodiments, R1Is unsubstituted unbranched C1-20An alkyl group. In certain embodiments, R1Is unsubstituted branched C1-20An alkyl group. In certain embodiments, R1Is of the formula:
Figure BDA0001614314770000431
wherein n is independently at each occurrence an integer from 0 to 20, inclusive.
In certain embodiments, R1Is of the formula:
Figure BDA0001614314770000432
wherein n is independently at each occurrence an integer from 0 to 20, inclusive.
In certain embodiments, R1Is of the formula:
Figure BDA0001614314770000433
in some embodiments of the present invention, the substrate is,R1is an optionally substituted aryl group, for example, an optionally substituted phenyl group. In certain embodiments, R1Is an unsubstituted aryl group, for example, an unsubstituted phenyl group. In certain embodiments, R1Is an optionally substituted heteroaryl group, for example, an optionally substituted 5-to 6-membered heteroaryl group or an optionally substituted 9-to 10-membered bicyclic heteroaryl group. In certain embodiments, R1Is an unsubstituted heteroaryl, e.g., an unsubstituted 5-to 6-membered heteroaryl or an unsubstituted 9-to 10-membered bicyclic heteroaryl.
L2And R2
The phosphate ester monomer and polyphosphate blocks described herein can comprise-L2R2. In certain embodiments, each-L in the copolymer2R2Are the same substituents. In certain embodiments, each-L in the copolymer2R2Is one of two specific substituents. In certain embodiments, each-L in the copolymer2R2Is one of three specific substituents. In certain embodiments, each-L in the copolymer2R2Is one of four specific substituents. In certain embodiments, each-L in the copolymer 2R2Is one of five specific substituents. In certain embodiments, each-L in the copolymer2R2Is one of six specific substituents. In certain embodiments, each-L in the copolymer2R2Is one of seven or more specific substituents.
As generally described herein, L2Each occurrence is optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene. In certain embodiments, L2Each independently is optionally substituted alkylene. In certain embodiments, L2Each independently is optionally substituted alkylene, and R2Each occurrence is independently an optionally substituted acyl group. In certain embodiments, L2Each independently being an unsubstituted alkylene group. At a certain pointIn some embodiments, L2Each independently is unsubstituted alkylene, and R2Each occurrence is independently an optionally substituted acyl group.
In certain embodiments, L2Is optionally substituted alkylene, e.g. optionally substituted C1-6Alkylene, optionally substituted C1-2Alkylene, optionally substituted C2-3Alkylene, optionally substituted C 3-4Alkylene, optionally substituted C4-5Alkylene or optionally substituted C5-6An alkylene group. In certain embodiments, L2Being unsubstituted alkylene, e.g. unsubstituted C1-6Alkylene, unsubstituted C1-2Alkylene, unsubstituted C2-3Alkylene, unsubstituted C3-4Alkylene, unsubstituted C4-5Alkylene or unsubstituted C5-6An alkylene group. In certain embodiments, L2Is methylene. In certain embodiments, L2Is ethylene, propylene, butylene, pentylene or hexylene.
In certain embodiments, L2Is optionally substituted alkenylene, e.g. optionally substituted C2-6An alkenylene group. In certain embodiments, L2Is unsubstituted alkenylene, e.g. unsubstituted C2-6An alkenylene group. In certain embodiments, L2Is vinylidene, allylidene or isoprenyl. In certain embodiments, L2Is optionally substituted alkynylene, e.g. optionally substituted C2-6Alkynylene radical. In certain embodiments, L2Is unsubstituted alkynylene, e.g. unsubstituted C2-6Alkynylene radical.
In certain embodiments, L2Is optionally substituted heteroalkylene, e.g. optionally substituted C1-6A heteroalkylene group. In some embodiments, L is2Is an unsubstituted heteroalkylene group, wherein the heteroalkylene group contains one oxygen atom. In some embodiments, L is 2Is an unsubstituted heteroalkylene group, wherein the heteroalkylene group contains one nitrogen atom. In certain embodiments, L2Is optionally substituted heteroalkenylene, for example,optionally substituted C1-6A heteroalkenylene group. In some embodiments, L is2Is unsubstituted heteroalkenylene, wherein heteroalkenylene comprises one oxygen atom. In some embodiments, L is2Is unsubstituted heteroalkenylene, wherein the heteroalkenylene comprises one nitrogen atom.
As generally described herein, R2Each occurrence is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORb、-N(Rb)2Or an oxygen protecting group. In certain embodiments, R2Each independently an optionally substituted acyl group. In certain embodiments, R2Each independently is optionally substituted acyl, and L2Each occurrence is independently optionally substituted alkylene.
In certain embodiments, R2Is an optionally substituted carbocyclic group, e.g. optionally substituted C3-6Carbocyclyl, optionally substituted C3-4Carbocyclyl, optionally substituted C4-5Carbocyclyl or optionally substituted C5-6A carbocyclic group. In certain embodiments, R2Being unsubstituted carbocyclic radicals, e.g. unsubstituted C 3-6A carbocyclic group. In some embodiments, R2Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In certain embodiments, R2Is an optionally substituted heterocyclic group, for example, an optionally substituted 3-to 6-membered heterocyclic group, an optionally substituted 3-to 4-membered heterocyclic group, an optionally substituted 4-to 5-membered heterocyclic group or an optionally substituted 5-to 6-membered heterocyclic group. In certain embodiments, R2Is an unsubstituted heterocyclic group, for example, an unsubstituted 3-to 6-membered heterocyclic group, an unsubstituted 3-to 4-membered heterocyclic group, an unsubstituted 4-to 5-membered heterocyclic group or an unsubstituted 5-to 6-membered heterocyclic group.
In certain embodiments, R2Is an optionally substituted aryl group, for example, an optionally substituted phenyl group. In certain embodiments, R2Is an unsubstituted aryl group, for example, an unsubstituted phenyl group. In certain embodiments, R2Is optionally substituted heteroaryl, e.g. optionally substituted 5-to 6-membered heteroarylOr an optionally substituted 9-to 10-membered bicyclic heteroaryl. In certain embodiments, R2Is an unsubstituted heteroaryl, e.g., an unsubstituted 5-to 6-membered heteroaryl or an unsubstituted 9-to 10-membered bicyclic heteroaryl.
In certain embodiments, R2Is optionally substituted acyl, e.g., -CHO, -CO 2H or-C (═ O) NH2. In certain embodiments, R2Is an optionally substituted carbonyl group. In certain embodiments, R2is-C (═ O) Rb、-C(＝O)ORb、-C(＝O)NH(Rb) or-C (═ O) N (R)b)2. In certain embodiments, R2is-C (═ O) RbAnd R isbIs an optionally substituted alkyl group, for example-C (═ O) Me. In certain embodiments, R2is-C (═ O) RbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R2is-C (═ O) RbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R2is-C (═ O) ORbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R2is-C (═ O) ORbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R2is-C (═ O) ORbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R2is-C (═ O) N (R)b)2And at least one RbIs an optionally substituted alkyl group. In certain embodiments, R2is-C (═ O) NHRbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R2is-C (═ O) NHRbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R2is-C (═ O) NHRbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R 2Is optionally substituted vinylcarbonyl (e.g., -C (═ O) CH ═ CH2、-C(＝O)CMe＝CH2). In some embodiments of the present invention, the substrate is,R2is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl).
In certain embodiments, R2is-ORbFor example-OH. In certain embodiments, R2is-ORbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R2is-ORbAnd R isbIs unsubstituted C1-6An alkyl group. In certain embodiments, R2is-ORbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R2is-ORbAnd R isbIs optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl. In certain embodiments, R2is-ORbAnd R isbUnsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl. In certain embodiments, R2is-ORbAnd R isbIs optionally substituted acyl, e.g. R2is-OC (═ O) Rb、-OC(＝O)ORbor-OC (═ O) N (R)b)2. In certain embodiments, R2is-ORbAnd R isbIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl).
In certain embodiments, R2is-N (R)b)2E.g., -NH2、-NHRb. In certain embodiments, R2is-NH (R)b) And R isbIs an optionally substituted alkyl group. In certain embodiments, R2is-N (R)b)2And at least one RbIs an optionally substituted alkyl group. In certain embodiments, R2is-NH (R)b) And R isbIs an unsubstituted alkyl group. In certain embodiments, R2is-N (R)b)2And at least one RbIs notA substituted alkyl group. In certain embodiments, R2is-NHRbAnd R isbIs an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl. In certain embodiments, R2is-NHRbAnd R isbIs unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl or unsubstituted heteroaryl. In certain embodiments, R2is-NHRbAnd R isbIs optionally substituted acyl, e.g. R2is-NHC (═ O) Rb、-NHC(＝O)ORbor-NHC (═ O) NHRb. In certain embodiments, R2is-N (R)b)2And at least one RbIs a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts). In certain embodiments, R2is-N (R)b)2And two R arebAre linked to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In certain embodiments, R 2is-N (R)b)2And two RbAre linked to form an unsubstituted heterocyclic ring or an unsubstituted heteroaryl ring.
In certain embodiments, -L2R2Is of the formula:
Figure BDA0001614314770000461
wherein n is an integer from 0 to 20, inclusive.
In certain embodiments, -L2R2Is of the formula:
Figure BDA0001614314770000462
wherein n is an integer from 0 to 20, inclusive.
In certain embodiments, -L2R2Is of the formula:
Figure BDA0001614314770000471
in certain embodiments, -L2R2Is of the formula:
Figure BDA0001614314770000472
R3
the polymer of formula (I) comprises R3. In certain embodiments, each R is3Are the same substituents. In certain embodiments, each R in the polymer3Is one of two specific substituents. In certain embodiments, each R in the polymer3Is one of three specific substituents. In certain embodiments, each R in the polymer3Is one of four specific substituents. In certain embodiments, each R in the polymer3Is one of five specific substituents. In certain embodiments, each R in the polymer3Is one of six specific substituents. In certain embodiments, each R in the polymer3Is one of seven or more specific substituents.
As generally described herein, R3Each occurrence is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR bor-N (R)b)2. In certain embodiments, R3Each occurrence is independently unsubstituted alkyl.
In certain embodiments, R3Is optionally substituted alkyl, e.g. optionally substituted C1-6Alkyl, optionally substituted C1-2Alkyl, optionally substituted C2-3Alkyl, optionally substituted C3-4Alkyl, optionally substituted C4-5Alkyl or optionally substituted C5-6An alkyl group. In certain embodiments, R3Is unsubstituted alkyl, e.g. unsubstituted C1-6Alkyl, unsubstituted C1-2Alkyl, unsubstituted C2-3Alkyl, unsubstituted C3-4Alkyl, unsubstituted C4-5Alkyl or unsubstituted C5-6An alkyl group. In certain embodiments, R3Is unsubstituted C1-20An alkyl group. In certain embodiments, R3Is unsubstituted C1-12An alkyl group. In certain embodiments, R3Is methyl. In certain embodiments, R3Is ethyl, propyl or butyl. In certain embodiments, R3Is haloalkyl, e.g., -CHF2、-CHCl2、-CH2CHF2、-CH2CHCl2. In certain embodiments, R3Is perhaloalkyl, e.g., -CF3、-CF2CF3、-CCl3. In certain embodiments, R3Is hydroxyalkyl, e.g., -CH2OH、-CH2CH2OH、-CH2ORb、-CH2CH2ORb. In certain embodiments, R3Is aminoalkyl, e.g., -CH2NH2、-CH2CH2NH2、-CH2NMe2、-CH2CH2NMe2、-CH2N(Rb)2、-CH2CH2N(Rb)2。
In certain embodiments, R3Is optionally substituted alkenyl, e.g. optionally substituted C 2-6An alkenyl group. In certain embodiments, R3Being unsubstituted alkenyl, e.g. unsubstituted C2-6An alkenyl group. In certain embodiments, R3Is vinyl, allyl or isoprenyl. In certain embodiments, R3Is optionally substituted alkynyl, e.g. optionally substituted C2-6Alkynyl. In certain embodiments, R3Is unsubstituted alkynyl, e.g. unsubstituted C2-6Alkynyl.
In certain embodiments, R3Is an optionally substituted aryl group, for example, an optionally substituted phenyl group. In certain embodiments, R3Is notSubstituted aryl groups, for example, unsubstituted phenyl. In certain embodiments, R3Is an optionally substituted heteroaryl group, for example, an optionally substituted 5-to 6-membered heteroaryl group or an optionally substituted 9-to 10-membered bicyclic heteroaryl group. In certain embodiments, R3Is an unsubstituted heteroaryl, e.g., an unsubstituted 5-to 6-membered heteroaryl or an unsubstituted 9-to 10-membered bicyclic heteroaryl.
In certain embodiments, R3Is optionally substituted acyl, e.g., -CHO, -CO2H or-C (═ O) NH2. In certain embodiments, R3Is an optionally substituted carbonyl group. In certain embodiments, R3is-C (═ O) Rb、-C(＝O)ORb、-C(＝O)NH(Rb) or-C (═ O) N (R)b)2. In certain embodiments, R 3is-C (═ O) RbAnd R isbIs an optionally substituted alkyl group, such as-C (═ O) Me. In certain embodiments, R3is-C (═ O) RbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3is-C (═ O) RbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R3is-C (═ O) ORbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R3is-C (═ O) ORbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3is-C (═ O) ORbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R3is-C (═ O) N (R)b)2And at least one RbIs an optionally substituted alkyl group. In certain embodiments, R3is-C (═ O) NHRbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R3is-C (═ O) NHRbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3is-C (═ O) NHRbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In some implementationsIn the scheme, R3Is optionally substituted vinylcarbonyl (e.g., -C (═ O) CH ═ CH2、-C(＝O)CMe＝CH2)。
In certain embodiments, R 3is-ORbFor example-OH. In certain embodiments, R3is-ORbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R3is-ORbAnd R isbIs unsubstituted C1-6An alkyl group. In certain embodiments, R3is-ORbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3is-ORbAnd R isbIs optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl. In certain embodiments, R3is-ORbAnd R isbUnsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl. In certain embodiments, R3is-ORbAnd R isbIs optionally substituted acyl, e.g. R3is-OC (═ O) Rb，-OC(＝O)ORbor-OC (═ O) N (R)b)2. In certain embodiments, R3is-ORbAnd R isbIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl).
In certain embodiments, R3is-N (R)b)2E.g., -NH2，-NHRb. In certain embodiments, R3is-NH (R)b) And R isbIs an optionally substituted alkyl group. In certain embodiments, R3is-N (R) b)2And at least one RbIs an optionally substituted alkyl group. In certain embodiments, R3is-NH (R)b) And R isbIs an unsubstituted alkyl group. In certain embodiments, R3is-N (R)b)2And at least one RbIs an unsubstituted alkyl group. In some embodimentsIn the scheme, R3is-NHRbAnd R isbIs an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl. In certain embodiments, R3is-NHRbAnd R isbIs unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl or unsubstituted heteroaryl. In certain embodiments, R3is-NHRbAnd R isbIs optionally substituted acyl, e.g. R3is-NHC (═ O) Rb、-NHC(＝O)ORbor-NHC (═ O) NHRb. In certain embodiments, R3is-N (R)b)2And at least one RbIs a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts). In certain embodiments, R3is-N (R)b)2And two RbLinked to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In certain embodiments, R3is-N (R)b)2And two RbAre linked to form an unsubstituted heterocyclic ring or an unsubstituted heteroaryl ring.
Synthesis of polyphosphate block copolymer
The block copolymers described herein may be prepared by sequential polymerization of the monomers corresponding to each block. For example, propylene oxide is polymerized, followed by polymerization of ethylene oxide beginning at the end of the polypropylene oxide, followed by polymerization of the phosphate ester monomer beginning at the end of the polypropylene oxide-polyethylene oxide polymer. In certain embodiments, a poloxamer comprising polyethylene and polypropylene blocks is treated with a phosphate ester monomer precursor. In some embodiments, the precursor is hydroxydioxolane (hydroxydioxaphospholane) or a dioxolane ester. In certain embodiments, the copolymer of formula (I) is prepared by contacting a polymer of formula (P) with a compound of formula (a) or a mixture of compounds of formula (a):
Figure BDA0001614314770000501
wherein p, q, r, s, t, G1、G2And Y is as defined herein.
In certain embodiments, the step of contacting the polymer of formula (P) with the compound of formula (a) is carried out in the presence of a catalyst. In some embodiments, the catalyst is an organic catalyst. In some embodiments, the catalyst is a base. In some embodiments, the catalyst is an organic base. In some embodiments, the catalyst is a non-nucleophilic base. In some embodiments, the catalyst is N, N-diisopropylethylamine (DIPEA, Hunig's base), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 2, 6-di-tert-butylpyridine, or phosphazenes (e.g., BEMP, t-Bu-P4). In some embodiments, the catalyst is 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
In some embodiments, the polymer is treated with a compound of formula (a-i):
Figure BDA0001614314770000502
mixtures of compounds of formula (A-i), e.g. with different R, may also be used1Or a single compound may be used.
In some embodiments, the polymer is treated with a compound of formula (a-ii):
Figure BDA0001614314770000511
mixtures of compounds of formula (A-ii) may also be used, e.g. with different R1Or a single compound may be used.
In some embodiments, the polymer is treated with a mixture of compounds of formulas (A-i) and (A-ii).
Figure BDA0001614314770000512
Mixtures of compounds of formula (A-i), e.g. with different R, may also be used1Or a single compound may be used. Mixtures of compounds of formula (A-ii) may also be used, e.g. with different R1Or a single compound may be used.
In certain embodiments, the first compound of formula (a) and the second compound of formula (a) are contacted with the copolymer of formula (P) simultaneously. For example, the compound of formula (A-i) and the compound of formula (A-ii) are added simultaneously to produce a polyphosphate block having a random monomer distribution. In other embodiments, the first compound of formula (a) is contacted with the copolymer of formula (P), followed by contacting the second compound of formula (a) with the product of contacting the compound of formula (P) with the first compound of formula (a). For example, a compound of formula (a-i) is added to produce a first polyphosphate block having a first monomer (e.g., a monomer of formula (M-i)), followed by a compound of formula (a-ii) to produce a second polyphosphate block having a second monomer (e.g., a monomer of formula (M-ii)).
The number of phosphate ester monomers in the resulting copolymer (e.g., variables P and t) will be determined by the reaction conditions, reaction time, and the number of equivalents of compound of formula (a) relative to the number of equivalents of compound of formula (P).
In certain embodiments, the copolymer may be further modified after the addition of the polyphosphate block. In some embodiments, one or more groups Y are modified after polymerization. In some embodiments, one or more groups Y are deprotected after polymerization. In some embodiments, the group G1Or G2Modified after polymerization.
Penetration enhancer
A permeation enhancer refers to any substance that increases the flux of a therapeutic agent across a barrier (e.g., a layer of cells, a membrane). In some embodiments, the barrier is skin. In some embodiments, the barrier is the tympanic membrane. Penetration enhancers may include, but are not limited to, surfactants (anionic, cationic, nonionic, zwitterionic), terpenes, aminoamides, aminoesters, azide-containing compounds, and alcohols. Permeation enhancers may include, but are not limited to, surfactants (anionic, cationic, nonionic, zwitterionic), terpenes, aminoamides, amino esters, azide-containing compounds, pyrrolidones, sulfoxides, fatty acids, and alcohols. In certain embodiments, the penetration enhancer is an anionic surfactant. In certain embodiments, the penetration enhancer is a cationic surfactant. In certain embodiments, the penetration enhancer is a nonionic surfactant. In certain embodiments, the penetration enhancer is a zwitterionic surfactant. In certain embodiments, the permeation enhancer is a terpene. In certain embodiments, the penetration enhancer is an aminoamide. In certain embodiments, the penetration enhancer is an amino ester. In certain embodiments, the permeation enhancer is an azide-containing compound. In certain embodiments, the penetration enhancer is a pyrrolidone. In certain embodiments, the permeation enhancer is a sulfoxide. In certain embodiments, the penetration enhancer is a fatty acid. In certain embodiments, the penetration enhancer is an alcohol. In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate. In certain embodiments, the penetration enhancer is sorbitan monooleate. In certain embodiments, the penetration enhancer is octoxynol-9. In certain embodiments, the penetration enhancer is diethyl sebacate. In certain embodiments, the penetration enhancer is sodium polyacrylate (molecular weight (MW) 2500000). In certain embodiments, the penetration enhancer is octyldodecanol.
Surfactant penetration enhancers may include, but are not limited to, sodium lauryl sulfate, ammonium lauryl sulfate, sodium laureth sulfate, cetyl trimethylammonium bromide, cetyl pyridinium chloride
Figure BDA0001614314770000521
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfateSulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl chembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure BDA0001614314770000522
Chlorinated dodecyl pyridine
Figure BDA0001614314770000523
Cetyl pyridinium chloride
Figure BDA0001614314770000524
Benzyl dimethyldodecyl ammonium chloride, benzyl dimethylmyristyl ammonium chloride, benzyl dimethylstearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and benzalkonium chloride. In some embodiments, the permeation enhancer is sodium lauryl sulfate, or sodium octyl sulfate. In some embodiments, the permeation enhancer is sodium lauryl sulfate. In some embodiments, the permeation enhancer is octyl-trimethyl-ammonium bromide or dodecyl-trimethyl-ammonium bromide. In some embodiments, the penetration enhancer is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In some embodiments, the penetration enhancer is benzalkonium chloride.
In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate (molecular weight (MW)2500000), or octyldodecanol. In certain embodiments, the penetration enhancer is sodium lauroyl sarcosinate. In certain embodiments, the penetration enhancer is sorbitan monooleate. In certain embodiments, the penetration enhancer is octoxynol-9. In certain embodiments, the penetration enhancer is diethyl sebacate. In certain embodiments, the penetration enhancer is sodium polyacrylate (molecular weight (MW) 2500000). In certain embodiments, the penetration enhancer is octyldodecanol.
In a plurality of entitiesIn embodiments, the penetration enhancer is an azone-like compound. In certain embodiments, the penetration enhancer is of the formula
Figure BDA0001614314770000531
Azone (e.g., laurone) analogous compounds of (a): in certain embodiments, the penetration enhancer is 1-benzyl-4- (2- ((1, 1-biphenyl) -4-yloxy) ethyl) piperazine.
In various embodiments, the penetration enhancer is a lipid. In certain embodiments, the lipid used in the composition is selected from the group consisting of phosphoglycerides; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleoyl phosphatidylethanolamine (DOPE); dioleoyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; a cholesterol ester; a diacylglycerol; diacylglycerol succinate; diphosphatidyl glycerol (DPPG); hexadecanol (hexadecanol); fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids, such as palmitic acid or oleic acid; a fatty acid; a fatty acid amide; sorbitan trioleate (Span 85) glycocholate; surfactin (surfactin); a poloxamer; sorbitan fatty acid esters, such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoyl phosphatidyl glycerol ester; stearamide; a dodecylamine; hexadecylamine; acetyl palmitate; glycerol ricinoleate; cetyl stearate; isopropyl myristate; tyloxapol; poly (ethylene glycol) 5000-phosphatidylethanolamine; and a phospholipid. In certain embodiments, the lipid used in the composition is selected from the group consisting of phosphoglycerides; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleoyl phosphatidylethanolamine (DOPE); dioleoyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; a cholesterol ester; a diacylglycerol; diacylglycerol succinate; diphosphatidyl glycerol (DPPG); cetyl alcohol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids, such as palmitic acid or oleic acid; a fatty acid; a fatty acid amide; sorbitan trioleate (Span 85) glycocholate; a surfactant; a poloxamer; fatty acid esters (e.g., methacrylic stearate); sorbitan fatty acid esters, such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoyl phosphatidyl glycerol ester; stearamide; a dodecylamine; hexadecylamine; acetyl palmitate; glycerol ricinoleate; cetyl stearate; isopropyl myristate; tyloxapol; poly (ethylene glycol) 5000-phosphatidylethanolamine; and a phospholipid. In certain embodiments, the penetration enhancer is a fatty acid ester. In certain embodiments, the penetration enhancer is methacrylic acid stearate. The lipid may be positively charged, negatively charged or neutral. In certain embodiments, the lipid is a combination of lipids. Phospholipids useful in the compositions of the present invention include negatively charged phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, diphosphatidylglycerol, poly (ethylene glycol) -phosphatidylethanolamine, dimyristoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dilauroylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dimyristoylphosphatidylphosphatidic acid, dipalmitoylphosphatidylserine, phosphatidylserine, and mixtures thereof. Useful zwitterionic phospholipids include phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lecithin, lysolecithin, lysophosphatidylethanolamine, cerebroside, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, di [ trans-9-octadecenoyl ] phosphatidylcholine (dielaioylphosphatidylcholine), dioleoylphosphatidylcholine, dilauroylphosphatidylcholine, 1-myristoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, 1-palmitoyl-phosphatidylcholine, 1-stearoyl-2-palmitoyl phosphatidylcholine, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, cephalin, dipalmitoylphosphatidylcholine, distearoylsphingomyelin, lysophosphatidylcholine, lysophosphatidylethanolamine, cerebroside, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, di-9-palmitoylphosphatidylcholine, di-phosphatidylcholine, di-palmitoyl-phosphatidylcholine, di-L, And mixtures thereof. Zwitterionic phospholipids constitute any phospholipid having an ionizable group in which the net charge is zero. In certain embodiments, the lipid is phosphatidylcholine.
Exemplary surfactants include, but are not limited to: sodium dioctyl sulfosuccinate, sodium lauryl sulfate, cocamidopropyl betaine, and sodium laureth sulfate, alkyl and alkyl ether sulfates (e.g., sodium cocoalkyltriethylene glycol ether sulfate; lithium tallow alkyltriethylene glycol ether sulfate; sodium tallow alkylhexaoxyethylene sulfate), salts of succinamates, salts of sulfosuccinamates (e.g., disodium N-octadecyl sulfosuccinamate, tetrasodium N- (1, 2-dicarboxyethyl) -N-octadecyl sulfosuccinamate, diamyl esters of sodium sulfosuccinates, dihexyl esters of sodium sulfosuccinates, dioctyl esters of sodium sulfosuccinates), olefin sulfonates, hydroxyalkane sulfonates, beta-alkoxyalkane sulfonates (e.g., potassium beta-methoxydecane sulfonate, sodium 2-methoxytridecane sulfonate, potassium 2-ethoxytetradecane sulfonate, Sodium 2-isopropoxyhexadecylsulfonate, lithium 2-tert-butoxytetradecylsulfonate, sodium beta-methoxyoctadecyl sulfonate, ammonium beta-N-propoxydodecylsulfonate), dioctyl ester of sodium sulfosuccinic acid, ethoxylated alkylsulfates, aliphatic secondary and quaternary amines (e.g., sodium 3-dodecylaminopropionate, N-alkyltaurine, stearamidopropyldimethylamine, diethylaminoethylstearamide, dimethylstearylamine, dimethylsoyamine, soyamine, myristylamine, tridecylamine, ethylstearylamine, N-tallow propane diamine, ethoxylated (5 moles E.O) stearylamine, dihydroxyethylstearylamine, and eicosyl behenylamine (arachidylbehenylamine)), alkylamphoglycinate (e.g., cocoamphoglycinate, lauryl amphocarboxyglycinate, ammonium N-propoxydecyldodecylsulfonate), and salts of sodium with sodium and potassium, Cocoamphocarboxyglycinate); alkyl amphopropionates (e.g., isostearyl amphopropionate, cocoamphocarboxypropionic acid); ethoxylated alkyl sulfates; an alkyl sulfate; aliphatic quaternary ammonium compounds (e.g., tallow propane diammonium dichloride, dialkyl dimethyl ammonium chloride, ditallo dimethyl ammonium methyl sulfate, dihexadecyl dimethyl ammonium chloride, di (hydrogenated tallow) di Methylammonium chloride, dioctadecyldimethylammonium chloride, biseicosyldimethylammonium chloride, bisdocosyldimethylammonium chloride, di (hydrogenated tallow) dimethylammonium acetate, dihexadecyldimethylammonium chloride, dihexadecyldimethylammonium acetate, ditallowadipropylammonium phosphate, ditallowadimethyammonium nitrate, and di (cocoalkylbenzylammonium chloride)); aliphatic phosphine compounds, aliphatic sulfonium compounds, alkylaminosulfonates, alkylbetaines (e.g., cocodimethylcarboxymethylbetaine, lauryldimethylcarboxymethylbetaine, lauryldimethyl alpha-carboxyethylbetaine, cetyldimethylcarboxymethylbetaine, lauryldi- (2-hydroxyethyl) carboxymethylbetaine, stearyldi- (2-hydroxypropyl) carboxymethylbetaine, oleyldimethylgamma-carboxypropylbetaine, lauryldi- (2-hydroxypropyl) alpha-carboxyethylbetaine), sulfobetaines (e.g., cocodimethylsulfopropylbetaine, stearyldimethylsulfonylpropylbetaine, lauryldimethylsulfoethylbetaine, lauryldi (2-hydroxyethyl) sulfopropylbetaine), alkylamidobetaines, 4- [ N, N-bis (2-hydroxyethyl) -N-octadecylammonium ]-butane-1-carboxylic acid salt; 5- [ S-3-hydroxypropyl-S-hexadecylsulfonium]-3-hydroxy-pentane-sulfate; 3- [ P, P-diethyl-P-3, 6, 9-trioxatetraxyphospham
Figure BDA0001614314770000551
]-2-hydroxy-propane-1-phosphate; 3- [ N, N-dipropyl-N-3-dodecyloxy-2-hydroxypropylammonium]-propane-1-phosphate; 3- (N, N-dimethyl-N-hexadecylammonium) propane-1-sulfonate; 3- (N, N-dimethyl-N-hexadecylammonium) -2-hydroxy-propane-1-sulfonate; 4- [ N, N-bis- (2-hydroxy-ethyl) -N- (2-hydroxydodecyl) ammonium]Butane-1-carboxylic acid salt; 3- [ S-Ethyl-S- (3-dodecyloxy-2-hydroxypropyl) sulfonium]-propane-1-phosphate; 3- [ P, P-dimethyl-P-dodecylphosphorus
Figure BDA0001614314770000552
]-propane-1-phosphonate; and 5- [ N, N-bis (3-hydroxypropyl) -N-hexadecylammonium]-2-hydroxypentane-1-sulfate, sodium 3-dodecylaminopropane sulfonate; alkyl amphoteric sulfonates; alkyl amphoteric sulfosuccinic acidA succinate salt; oleoyl amphopropyl sulfonate and cocoyl amphopropyl sulfonate; a polyethylene oxide condensate; long chain tertiary phosphine oxides; long chain dialkyl sulfoxides; silicone copolyols (e.g. dimethicone copolyol), stearamide Diethanolamide (DEA), cocamide Monoethanolamide (MEA), glycerol monooleate, sucrose stearate, ceteth-2, poloxamer 181, hydrogenated tallow amide DEA, polyoxyethylene 4 sorbitol beeswax derivatives (ATLAS 6-1702), polyoxyethylene 2 cetyl ether (BRIJ 52), polyoxyethylene 2 stearyl ether (BRIJ 72), polyoxyethylene 2 oleyl ether (BRIJ 92), polyoxyethylene 2 oleyl ether (BRIJ 93), sorbitan monopalmitate (SPAN 40), sorbitan monostearate (SPAN 60), sorbitan tristearate (SPAN 65), sorbitan monooleate, NF (SPAN 80) sorbitan trioleate (SPAN 85), fluorinated alkyl quaternary ammonium iodides; mixed mono-and bis-perfluoroalkyl ammonium phosphates; mixed mono-and bis-perfluoroalkyl ammonium phosphate salts complexed with aliphatic quaternary methyl sulfates; ammonium salt of perfluoroalkyl sulfonic acid; mixed telomer diethanolamine phosphate salts; a perfluoroalkyl sulfonic acid amine; ammonium perfluoroalkylsulfonate; a potassium perfluoroalkylsulfonate; a fluorinated alkyl carboxylic acid potassium salt; ammonium perfluoroalkylsulfonate; and ammonium perfluoroalkylcarboxylates; dioctyl sodium sulfosuccinate; magnesium dioctyl sulfosuccinate; ammonium dioctyl sulfosuccinate; magnesium lauryl sulfate; ammonium lauryl sulfate; sodium cocoamidopropyl betaine dinonyl sulfosuccinate; sodium alpha-olefin sulfonate; sodium laureth sulfate; magnesium laureth sulfate; ammonium laureth sulfate; cocamidopropyl betaine; polyethoxylated glycol ethers of glyceryl isostearate; polyethoxylated glycol ethers of glycerol monooleate; PEG-30 glyceryl isostearate; polyoxyethylene glyceryl monooleate; polyethylene glycol; PPG-18; PPG-10; 18 polydimethylsiloxane; 1 dimethicone (1 dimethicon); cetyl polyethylene glycol; glyceryl monostearate; laureth-23; and PEG 75 lanolin. In certain embodiments, the surfactant is a silicon-containing compound. Exemplary silicon-based detergents, emulsifiers or surfactants useful in cosmetic compositions include polydimethylsiloxane, cyclopentasiloxane, cyclohexasiloxane Siloxanes, PEG/dimethicone copolymer, PPG/dimethicone copolymer, phenyl trimethicone, alkyl silicones, amodimethicone (amodimethicone), silicone quat-18, and dimethiconol.
Terpene permeation enhancers may include, but are not limited to, limonene, cymene, pinene, camphor, menthol, complex, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, beta-caryophyllene, eucalyptol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, and ethylpiperazine carboxylate. Any terpene or terpenoid may be used as a permeation enhancer in the compositions of the present invention. In certain embodiments, the permeation enhancer is limonene.
Alcohol penetration enhancers may include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-amyl alcohol. In certain embodiments, the penetration enhancer is a compound having more than one hydroxyl group (e.g., glycerol). For example, the permeation enhancer may include two, three, four, five, or more hydroxyl groups. In certain embodiments, the penetration enhancer is a hydroxyl-containing polymer.
In certain embodiments, the aminoamide or aminoester permeation enhancer is an anesthetic. The aminoamide and aminoester permeation enhancers can include, but are not limited to, bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomecaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, perocaine, and tricaine. In certain embodiments, the penetration enhancer is bupivacaine.
In certain embodiments, the composition comprises a combination of penetration enhancers. In certain embodiments, the combination comprises the same type of penetration enhancer (e.g., both surfactants, both terpenes). In certain embodiments, the combination comprises different types of penetration enhancers (e.g., surfactants and terpenes). In certain embodiments, the combination comprises a surfactant and a terpene. In certain embodiments, the combination comprises a cationic surfactant and a terpene. In certain embodiments, the combination comprises an anionic surfactant and a terpene. In certain embodiments, the combination comprises a nonionic or zwitterionic surfactant and a terpene.
In certain embodiments, the combination comprises a surfactant and an amino amide or amino ester. In certain embodiments, the combination comprises a cationic surfactant and an amino amide or amino ester. In certain embodiments, the combination comprises an anionic surfactant and an aminoamide or aminoester. In certain embodiments, the combination comprises a nonionic or zwitterionic surfactant and an aminoamide or aminoester. In certain embodiments, the combination comprises a terpene and an amino amide or amino ester. In some embodiments, the aminoamide or aminoester is an anesthetic. In some embodiments, the anesthetic is bupivacaine.
In some embodiments, the penetration enhancer is a combination of compounds selected from two or three of groups (i) to (iii):
(i) a surfactant selected from: sodium dodecyl sulfate, ammonium lauryl sulfate, sodium laureth sulfate, cetyl trimethyl ammonium bromide, and cetyl pyridinium chloride
Figure BDA0001614314770000571
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, tridecyl phosphate Sodium; decyl dimethyl ammonium propane sulfonate, oleyl chembetaine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure BDA0001614314770000572
Chlorinated dodecyl pyridine
Figure BDA0001614314770000573
Cetyl pyridinium chloride
Figure BDA0001614314770000574
Benzyl dimethyldodecylammonium chloride, benzyl dimethylmyristylammonium chloride, benzyl dimethylstearoylammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and benzalkonium chloride;
(ii) a terpene selected from: limonene, cymene, pinene, camphor, menthol, complene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, beta-caryophyllene, eucalyptol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate or ethylpiperazine carboxylate;
(iii) And an anesthetic selected from: bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomecaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, perocaine, and tricaine.
In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium octyl sulfate, sodium dodecyl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20 or polysorbate 80 as a surfactant. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the above-listed groups (i) to (iii) and comprises sodium lauryl sulfate as a surfactant. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the above-listed groups (i) to (iii), and comprises limonene as a surfactant. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium lauryl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20 or polysorbate 80 as a surfactant, and limonene as a terpene. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium lauryl sulfate as a surfactant and limonene as a terpene. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium lauryl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20 or polysorbate 80 as a surfactant, and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium lauryl sulfate as a surfactant and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises limonene as a terpene and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium lauryl sulfate, octyltrimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20 or polysorbate 80 as a surfactant, limonene as a terpene, and bupivacaine as an anesthetic. In some embodiments, the penetration enhancer is a combination of compounds of at least two of the groups (i) to (iii) listed above and comprises sodium lauryl sulfate as a surfactant, limonene as a terpene and bupivacaine as an anesthetic.
In certain embodiments, the weight percentage of penetration enhancer in the composition is from about 0.1% to about 1%, from about 1% to about 3%, or from about 3% to about 10%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 0.1% to about 1%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 1% to about 3%. In certain embodiments, the weight percentage of the penetration enhancer in the composition is from about 0.1% to about 10%. In certain embodiments, the weight percentage of penetration enhancer in the composition is from 0.1% to about 1%, from about 1% to about 2%, from about 2% to about 3%, from about 3% to about 4%, from about 4% to about 5%, from about 5% to about 6%, from about 6% to about 7%, from about 7% to about 8%, from about 8% to about 9%, or from about 9% to about 10%.
In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is from about 0.1% to about 3%. In some embodiments, the weight percentage of sodium lauryl sulfate in the composition is about 1%. In some embodiments, the weight percentage of bupivacaine in the composition is from about 0.1 to about 3%. In some embodiments, the weight percentage of bupivacaine in the composition is about 0.5%. In some embodiments, the weight percentage of limonene in the composition is about 0.1% to about 3%. In some embodiments, the weight percentage of limonene in the composition is about 0.5%.
Therapeutic agents
The therapeutic agent can be any agent useful for treating any otic disorder or symptom of an otic disorder. The therapeutic agent may include an antimicrobial agent. Therapeutic agents may include, but are not limited to, antimicrobials, antibiotics, anesthetics, anti-inflammatory agents, analgesics, anti-fibrotic agents, anti-sclerosing agents, and anticoagulants. Therapeutic agents may include, but are not limited to, antibiotics, anesthetics, anti-inflammatory agents, analgesics, anti-fibrotic agents, anti-sclerosing agents, and anticoagulants. In certain embodiments, the therapeutic agent is an antimicrobial agent. In certain embodiments, the therapeutic agent is an antibiotic agent. In certain embodiments, the therapeutic agent is an anesthetic. In certain embodiments, the therapeutic agent is an anti-inflammatory agent. In certain embodiments, the therapeutic agent is an analgesic. In certain embodiments, the therapeutic agent is an anti-fibrotic agent. In certain embodiments, the therapeutic agent is an anti-sclerosing agent. In certain embodiments, the therapeutic agent is an anticoagulant.
In various aspects, the therapeutic agent can comprise from about 0.01% to about 10% of the composition. In various embodiments, the therapeutic agent can comprise from about 0.01% to about 1% of the composition, from about 1% to about 2% of the composition, from about 2% to about 3% of the composition, from about 3% to about 4% of the composition, from about 4% to about 5% of the composition, from about 5% to about 6% of the composition, from about 6% to about 7% of the composition, from about 7% to about 8% of the composition, from about 8% to about 9% of the composition, or from about 9% to about 10% of the composition.
The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the particular compound, its mode of administration, its mode of activity, the condition being treated, etc. The compositions described herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily amount of the compounds and compositions will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the particular compound used; the specific composition adopted; the age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the particular compound used; the duration of the treatment; drugs used in combination or concomitantly with the specific compounds used; and similar factors well known in the medical arts.
In certain embodiments, the therapeutic agent is an anti-inflammatory agentA microbial agent. In certain embodiments, the therapeutic agent is an antibiotic. Any antibiotic may be used in the system of the invention. In certain embodiments, the antibiotic is approved for use in humans or other animals. In certain embodiments, the antibiotic is approved for use by the U.S. food and drug administration. In certain embodiments, the antibiotic may be selected from: cephalosporins, quinolones, polypeptides, macrolides, penicillins and sulfonamides. Exemplary antibiotics can include, but are not limited to, ciprofloxacin, cefuroxime, cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefbuperam, ceftizoxime, ceftriaxone, cefepime, cephapirin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, taenia, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mechlorcillin, cefaclonifloxacin, cefaclonixin, cefuroxime, cefepime, cefixime, cefditorexin, cefditerol, and a, cefprozil, cefuroxime, Mezlocillin, methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, mafenide, sulfacetamide, sulfamethylthiadiazole, sulfasalazine, and sulfa-isopropyl
Figure BDA0001614314770000601
Azole, trimethoprim and trimethoprim-sulfamethoxazole
Figure BDA0001614314770000602
And (3) azole.
In certain embodiments, the antibiotic is a quinolone. In certain embodiments, the antibiotic is a carbapenem. In certain embodiments, the antibiotic is. In certain embodiments, the antibiotic is amoxicillin, azithromycin, cefuroxime, ceftriaxone, trimethoprim, levofloxacin, moxifloxacin, meropenem, or ciprofloxacin. In some embodiments, the antibiotic is ciprofloxacin. In some embodiments, the antibiotic is ciprofloxacin and pharmaceutically acceptable salts thereof. In some embodiments, the antibiotic is ciprofloxacin hydrochloride. In some embodiments, the antibiotic is levofloxacin.
Exemplary antibiotics include, but are not limited to: abamectin, actinomycin (e.g. actinomycin A, actinomycin C, actinomycin D, aureomycin (Aurantin)), alafloxacin mesylate, amikacin sulphate, aminosalicylic acid, anthracyclines (e.g. aclarubicin, doxorubicin, epirubicin, idarubicin), antimycin (e.g. antimycin A), abamectin, BAL 30072, bacitracin, bleomycin, cephalosporins (e.g. 7-aminocephalosporanic acid, 7-aminodesacetoxycephalosporanic acid, cefaclor, cefadroxil, cefamandole, cefazolin, cefepime, cefixime, cefmetazole, cefoperazone, cefotiam, cefoxitin, pirome, cefpodoxime proxetil, ceftazidime, cefsulodin sodium, ceftazidime, ceftizoxime, ceftriaxone, amitrazone, amitraz, cefuroxime, cephalexin, ceftiofur, cephalosporin C, cephalothin sodium, cefapirin, cefradine), ciprofloxacin, enrofloxacin, clarithromycin, clavulanic acid, clindamycin, colicin, cyclosporine (e.g., cyclosporin A), dalfopristin/quinupristin, daunorubicin, doxorubicin, epirubicin, GSK 1322322, geneticin, gentamicin sulfate, gramicidin (e.g., gramicidin A), gapafloxacin hydrochloride, ivermectin, kanamycin (e.g., kanamycin A), lasalociclovir, doxorubicin, linezolid, lomefloxacin, lovastatin, MK 5, meropenem, mevastatin, mithramycin, mitomycin, monotomycins, natamycin, neocarzinan, neomycin (e.g., neomycin sulfate), Nystatin, oligomycin, olivomycin, pefloxacin, penicillin (e.g. 6-aminopenicillanic acid, amoxicillin-clavulanic acid, ampicillin sodium, azlocillin, carbenicillin, cefoxitin, ceftazidime, cloxacillin, dicloxacillin Penicillin, mecillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G potassium, procaine penicillin G, penicillin G sodium, penicillin V, piperacillin-tazobactam, sulbactam, tazobactam, ticarcillin), phleomycin, polymyxin (e.g., colistin, polymyxin B), pyocin (e.g., pyocin R), RPX 7009, rapamycin, ristocetin, saromycin, sparfloxacin, spectinomycin, spiramycin, streptogramin, streptoverticcin, tedizolid phosphate, teicoplanin, telithromycin, tetracyclines (e.g., tetracycline phosphate double salt, demeclocycline, polycyclocycline, doxycycline monohydrate, minocycline, oxytetracycline hydrochloride, tetracycline hydrochloride), trichostatin A, oxytetracycline, and, Trovafloxacin, tunicamycin, brevibacterium casein, validamycin, (-) -florfenicol and sulfacetamide
Figure BDA0001614314770000611
Azole, actinomycin, amikacin sulfate, benzethonium chloride, cetrimide, chelerythrine, chlorhexidine (e.g., chlorhexidine gluconate), chlorhexidine acetate, chlorhexidine gluconate, chlorothalonil, and sulfamethoxazole
Figure BDA0001614314770000612
Oxazole, dichlorophen, didecyldimethylammonium chloride, dihydrostreptomycin, enoxacin, ethambutol, fleroxacin, furazolidone, methylisothiazolinone, glycerol monolaurate,
Figure BDA0001614314770000613
Quinamic acid, povidone iodine, spirobicidal agents (e.g., arsinamine, neoarsinamine), sulfaquinoxaline, thiamphenicol, tinidazole, triclosan, trovafloxacin, tuberculosis inhibitors (e.g., 4-aminosalicylic acid, AZD 5847, aminosalicylic acid, ethionamide), vidarabine, zinc pyrithione, and zirconium phosphate.
In certain embodiments, the therapeutic agent is a drug approved by the Food and Drug Administration (FDA) for the treatment of an infection or infectious disease. Exemplary FDA-approved agents include, but are not limited to: avycaz (ceftazidime-abamectin), Cresemba (isavuconazole sulfate), Evoaz (atazanavir and cobicistat), Prezcobix (diroravir and cobicistat), Dalvanine (dalbavancin), Harvoni (Ledipasvir and Sofebuvir), Impavido (miltefosine), Jublia (efoconazole), Kerydin (tavaborole), Metronidazole (Metronidazole), Orbativ (Orivacin), Rapivab (Palamivir injection), Sivextro (Tedizolidamine phosphate), Triumeq (abacavir, Dutrovir and Lamivudine), Viekira Pak (Oxetavir, ritivir, ritonavir and Dalatasvir), Xtoro (finafloxacin), Cytenovir (Abiravir + Cytica), valacyclovir (Aciflavine), valacyclovir (Sirtulazarix), valacyclovir (Acivavir), valacyclovir (Sirtulazarix (Acivavir), valacyclovir (Sirtulazine), valacyclovir (Acinetova (Sirtulazine), valacyclovir), valacitretinovir (Acinetova (Sirtusin), valacyclovir), valaci (Sirtus (Sirtula), valaci (Sirtula), valacyclovir), valaci (Sirtula), valacitrex (Sirtula), valtrex (Sirtula), valacitrex (Sirtula), valacitretino (Sirtula), and valacil (Sirtula), and valacitrex (Sirtula), valtrexas (Sirtula), valtrex (valacil) and valtrexas (valtrex (Sirtula), valtrex (valacitrex (valtretam (valacitretam (valla), valtretam (valtrex (valacia), and valtretam) and valacitrex (valtrex), valtrex (valtretam), valtretam) and valtrex (valtrex) and valtretam (valtretam) and valtrex (valtrex), valtrex (valtretam) and valtrex (valtretam) and valtrex (valtretam) and valtretam (valtretam) and valtrex (valtretam) and valtretame), valtretam (valtretame), and valtretame), valtretam (valtretamb (valtretam) and valtretamb (valtretamb), valtretamb (valtretam) and valtretam (valtretamb (valtretame), tretam) and valtretam (valtretam) and valtretam), Fulyzaq (crofelemer), Jetrea (oxclevin), Linzess (linaclotide), Qnasl (beclomethasone dipropionate) nasal aerosol, Sirturo (Bedaquinoline), Skline (ivermectin), stribil (Eltegravir, cobicistat, emtricitabine, tenofovir dipivoxil fumarate), Tudorza pressaire (Addenum bromide inhalation powder), Complera (emtricitabine/Ripivirine/Tenofovir disoproxil fumarate), Dificid (fidaxomycin), Edurant (Ripidulin), Eylea (Aspirin), Firazyr (Eltebant), Gralisine (Gabavudine), Incivir (Telavilavir), Virillis (Paclipriris (Pacli), Egriffruta (Terifolilin), Telecavir (Telaprepivir), Jetta (Reliar), Jerta (Relat), Jetta (Relat), Jettavir (Zletretane (Azithromazine), hydrochloric acid (Azithromycin), Vitretin (Azithromycin), Vitreta (Azithrombin), Vitreta), Proteosine), Vitreta (Benzid (Azithm), Proteosine (Benzid), Proteosine (Benzid), Proteflut), Proteosine (Benzid), Proteosine (Benzid), Proteosine (Benzid), and the like), and the salt), and the like), and the salts of the compounds, Viread (tenofovir dipivoxil fumarate), isentres (raltegravir), Selzentry (maraviroc), verazint (valvavir), Veramyst (fluticasone furoate), XYzal (levocetirizine hydrochloride), Eraxis (anidulafungin), Noxafil (posaconazole), Prezista (darunavir), Tyzeka (tibifadine), Veregen (kunecatechins), Baraclude (entecavir), Fuzeon (enverdigiland), Lexiva (calcium fosamprenavir), Reyataz (atazanavir sulfate), desloratadine (Clarinex), Hepsera (adefovir), Pegasys (polyethylene glycol interferon alpha-2 a), Epiflaviran (Sustava), Vf (voriconazole), Zelmonox (tiger's acid), Canadelox (Canadex), valacil (valacyclovir hydrochloride), valacyclovir hydrochloride (valacyclovir), valacil (valacyclovir), valacyclovir hydrochloride (valacyclovir), valtrex (valacyclovir), valtrexat (valacyclovir), valtrevapristin (valtrex), valtrex (valtrewix), valtretino-2 a), valtretino (valtretino), valtretinol), valtretino (valtretinox (valtretinose), valtretino (valtretinose), valtretino (valtretinose), valtretino), tretinose (e), tretino (e), tretinol), tretino (e, tretinol), tretinol), tretino (e, tretinol), tretinol (e, tretinol), tretinol, tretino, Xigris (drotrecogin alpha), ABREVA (behenyl alcohol), cefazolin, Kaletra, hymexazol (Lamisil) hydrochloride, Lotrisone (clotrimazole/betamethasone dipropionate), roxithromycin (Lotronex) hydrochloride, Trizivir (abacavir sulfate, lamivudine, zidovudine AZT), Synercid, Synagis, Viroptic, Aldara (imiquimod), Bactroban, Ceftin (cefuroxime axetil), Cobivir, Condylox (posofilox), Famvir (famciclovir), Floxin, Fortovase, INTRGEN (interferon alfacon-1), Intron A (interferon alpha-2 b, recombinant), Mebutilinifen hydrochloride, Norvir (ritonavir), Rescref, Restricine (racquinavir), Alrafacil, Alfelone (Acifacon-1), Altrovudine (Epsilodine hydrochloride), Toxodine (Aciflavine hydrochloride), Toxodine hydrochloride (Eptifine A-N-2 b), recombinant, Atrovent (ipratropium bromide), Augmentin (amoxicillin/clavulanate), Crixivan (indinavir sulfate), Elmiron (pentosan polysulfate sodium), Havrix, Leukine (sargrastim), Merrem (meropenem), nasort AQ (triamcinolone acetonide acetate), Tavist (clemastine fumarate), vancnase AQ, Videx (didanosine), Viramune (nevirapine), cisume (Zithromax) (azithromycin), Cedax (ceftibuten), clarithromycin (Biaxin), Epivir (lamivudine), inviriquinavir (saquinavir), Valtrex (valacyclovir hydrochloride), ztec (cetirizine hydrochloride), acyclovir, cubilcin (daptomycin), fazicin (gibacin), albenzazole (azazoline), anilox (azalide), azithromycin sustained release ophthalmic suspension (azazide XL (afloxacin), azithromycin (azalide (benzathine), azithromycin sustained release ophthalmic drug release (azalide XL (antibiotic), and antibiotic (antibiotic), antibiotic (antibiotic, antibiotic, Cayston (aztreonam), Cleocin (clindamycin phosphate), Doribax (doripenem), Dynaba, Flagyl ER, Ketek (telithromycin), Moxatag (amoxicillin), Rapalygmus (sirolimus), Restasis (cyclosporine), Tindamax (tinidazole), Tygacil (tigecycline), and Xifaxan (rifaximin).
In certain embodiments, the therapeutic agent is an anesthetic. Any anesthetic may be used in the system of the present invention. In certain embodiments, the anesthetic is approved for use in humans or other animals. In certain embodiments, the anesthetic is approved for use by the U.S. food and drug administration. Exemplary anesthetics can include, but are not limited to, bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomecaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, cocaine, and tricaine. In certain embodiments, the anesthetic is bupivacaine.
In certain embodiments, the therapeutic agent is an anti-inflammatory agent. The anti-inflammatory agent may be a non-steroidal anti-inflammatory agent or a steroidal anti-inflammatory agent. In certain embodiments, the therapeutic agent is a steroidal anti-inflammatory agent. In certain embodiments, the therapeutic agent is a steroid. Exemplary anti-inflammatory agents may include, but are not limited to, acetylsalicylic acid, amoxiprin, paracetamol/benorilate, choline magnesium salicylate, diflunisal, ethacrysal, faislamine, methyl salicylate, magnesium salicylate, salicylate, salicylamide, diclofenac, acetylclofenamic acid, acemetacin, alclofenac, bromfenac, etodolac, indomethacin, nabumetone, olmesalamine, progluminic acid, tolmetin, ibuprofen, alminoprofen, benzene
Figure BDA0001614314770000641
Loxfen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flurnoprofen, flurbiprofen, ibuprofene, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, aminoantipyrine, apazone, clofezone, ketophenylbutazone, analgin, moNon-phenylbutazone, oxyphenbutazone, fenoxanone, phenylbutazone, sulpirenone, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone acetonide, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, and aldosterone.
In various embodiments, combinations of various penetration enhancers and therapeutic agents have been observed to have synergistic and enhanced efficacy. In various aspects, such combinations may include, but are not limited to, ciprofloxacin and limonene. In various aspects, such combinations may include, but are not limited to, ciprofloxacin and sodium lauryl sulfate. In various aspects, such combinations may include, but are not limited to, sodium lauryl sulfate, limonene, bupivacaine, and ciprofloxacin. In various aspects, such combinations may include, but are not limited to, sodium lauryl sulfate, limonene, and ciprofloxacin.
In another aspect, provided herein is a pharmaceutical composition comprising at least one compound as described herein, or a pharmaceutically acceptable derivative thereof. In certain embodiments, the pharmaceutical composition comprises a combination of therapeutic agents. In certain embodiments, the composition comprises an antibiotic and an additional therapeutic agent. In certain embodiments, the composition comprises an antibiotic agent and an anti-inflammatory agent. In other embodiments, the composition comprises an antibiotic agent and an anesthetic agent. In certain embodiments, the composition comprises more than one antibiotic agent.
In certain embodiments, the additional therapeutic agent is an anti-inflammatory agent (e.g., a steroid). In certain embodiments, the first therapeutic agent is an antibiotic and the additional therapeutic agent is an anti-inflammatory agent. In certain embodiments, the first therapeutic agent is an antibiotic and the additional therapeutic agent is a steroid. Steroids include, but are not limited to, cortisol, hydrocortisone acetate, cortisone acetate, thiohydrocortisone pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide acetate, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinolone (fluocinonide), fluocinolone acetonide acetate, halcinonide, betamethasone sodium phosphate, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, halomethasone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednisolone, clobetasol-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate, fluocortolone pivalate, fluprednide acetate, hydrocortisone-17-butyrate, hydrocortisone-17-acetate, hydrocortisone, Hydrocortisone-17-butyrate propionate (buteprate), ciclesonide, and prednisone ester. In some embodiments, the additional anti-inflammatory agent is dexamethasone.
In certain embodiments, the additional therapeutic agent is a beta-lactamase inhibitor. In certain embodiments, the first therapeutic agent is an antibiotic (e.g., a beta-lactam) and the additional therapeutic agent is a beta-lactamase inhibitor. Beta-lactamase inhibitors include, but are not limited to, avibactam, clavulanic acid, tazobactam, and sulbactam. The beta-lactamase inhibitor may be used in particular in a composition comprising a beta-lactam antibiotic. The beta-lactamase inhibitor may increase the efficacy of the beta-lactam antibiotic or allow the beta-lactam antibiotic to be present in the composition at a lower concentration than a composition without the beta-lactamase inhibitor.
In addition, the pharmaceutical compositions can be administered to humans and other animals after formulation with a suitable pharmaceutically acceptable carrier in a desired dosage.
Dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, and flavoring agents. In certain embodiments, the composition comprises a solubilizing agent, such as Cremophor (Cremophor), an alcohol, an oil, a modified oil, a glycol, a polysorbate, a cyclodextrin, a polymer, and combinations thereof.
It will also be appreciated that the compositions described herein may be used in combination therapy, i.e., the compounds and pharmaceutical compositions may be administered concurrently with, before or after one or more other desired therapeutic agents or medical procedures. The particular combination of treatments (therapeutic agents or procedures) used in the combination regimen will take into account the compatibility of the desired therapeutic agent and/or procedure and the desired therapeutic effect to be achieved. It will also be appreciated that the treatments employed may achieve the desired effect against the same disease (e.g., the compounds of the invention may be administered concurrently with another anti-cancer agent), or they may achieve different effects (e.g., control of any adverse effects).
In certain embodiments, the composition comprises a diagnostic agent. In some embodiments, the diagnostic agent is an X-ray contrast agent. In some embodiments, the diagnostic agent comprises a radioisotope. In some embodiments, the diagnostic agent is a dye.
Other additives
In certain embodiments, the composition comprises one or more additional additives. For example, the additional additive may be a diluent, binder, preservative, buffer, lubricant, fragrance, antimicrobial or oil.
Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dicalcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.
Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilages of isapol skin (husk)), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl celluloseHydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinylpyrrolidone), magnesium aluminum silicate
Figure BDA0001614314770000661
And larch arabinogalactans), alginates, polyethylene oxides, polyethylene glycols, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohols, and/or mixtures thereof.
Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. In certain embodiments, the preservative is benzalkonium chloride.
Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
Exemplary acidic preservatives include vitamin a, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
Other preservatives include tocopherol, tocopheryl acetate, deferoxamine mesylate (desoxamine mesylate), cetrimide, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ethylenediamine, Sodium Lauryl Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, sodium metabisulfite, sodium salt, sodium,
Figure BDA0001614314770000662
Plus、
Figure BDA0001614314770000663
Methyl p-hydroxybenzoate,
Figure BDA0001614314770000664
115、
Figure BDA0001614314770000665
II、
Figure BDA0001614314770000666
And
Figure BDA0001614314770000667
exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, calcium hydrogen phosphate, phosphoric acid, calcium phosphate, calcium hydroxide (calcium hydroxide phosphate), potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and mixtures thereof.
Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
Exemplary natural oils include almond, avocado, babassu, bergamot, blackcurrant seed, borage, juniper, chamomile, canola (canola), caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba oil, macadamia, lavender, lemon, litsea cubeba, macadamia (macadamia nut), mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, tilapia (oranroughy), palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, soybean, soy butter, sunflower, silicone, sunflower, castor oil, canola, black pepper, black sesame, canola, black sesame, black sesame, coffee, black sesame, corn, black sesame, and sesame, black sesame, etc., black sesame, etc., black sesame, etc., and black sesame, etc., and so, Tea tree, thistle, toona sinensis (tsubaki), vetiver, walnut and wheat germ. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
The compositions may include water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Formulations suitable for administration (e.g., to the ear canal) include, but are not limited to, liquid and/or semi-liquid preparations, such as liniments, lotions, oil-in-water and/or water-in-oil emulsions (e.g., creams, ointments, and/or pastes), and/or solutions and/or suspensions. While the topically administrable formulation may, for example, contain from about 1% to about 10% (weight/weight) of the therapeutic agent, the concentration of the therapeutic agent may be as high as the solubility limit of the active ingredient in the solvent.
Polysaccharide matrix forming agent
Also provided herein are compositions comprising a polysaccharide-based matrix-forming agent. The matrix forming agent may form a hydrogel by cross-linking a first polysaccharide derivative and a second polysaccharide derivative, wherein the first and second polysaccharides are different. For example, the first polysaccharide may be a Hyaluronic Acid (HA) derivative comprising a first cross-linkable functional group, and the second polysaccharide may be a cellulose derivative comprising a second cross-linkable functional group. As another example, the first polysaccharide is an HA derivative comprising a first cross-linkable functional group, and the second polysaccharide is a dextran derivative comprising a second cross-linkable functional group. In certain embodiments, the first crosslinkable functional group and the second crosslinkable functional group are selected from amine, amide, aldehyde, ester, ketone, hydroxyl, hydrazine, hydrazide, maleimide, or thiol. In some embodiments, the first functional group is an amine and the second functional group is an aldehyde. In some embodiments, the first functional group is an amine and the second functional group is a ketone. In some embodiments, the first functional group is an amine, hydroxyl, or thiol group, and the second functional group is an ester. In some embodiments, the first functional group is maleimide and the second functional group is a thiol. In some embodiments, the first functional group is a hydrazine or hydrazide and the second functional group is an aldehyde or ketone. In some embodiments, the first functional group is a hydrazide and the second functional group is an aldehyde.
The hydrogel may be formed by cross-linking a first polysaccharide derivative and a second polysaccharide derivative, wherein the first polysaccharide and the second polysaccharide are the same, and wherein the first polysaccharide derivative comprises a first cross-linkable functional group and the second polysaccharide derivative comprises a second cross-linkable functional group, wherein the first cross-linkable functional group and the second cross-linkable functional group are capable of cross-linking with each other. The polysaccharide may be, for example, a glycosaminoglycan, HA, cellulose, dextran, or a derivative of any of the foregoing.
HA, also known as hyaluronan or hyaluronate, is a non-branched polysaccharide containing a repeating disaccharide subunit consisting of N-acetyl-D glucosamine and D-glucuronic acid. (see Laurent, T.C. (eds.), Chemistry, Biology and Medical Applications of Hyaluronan and Its Derivatives, London: Portland Press, 1998). HA also refers to any salt thereof, such as sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, and the like. The term "HA derivative" refers to HA that HAs been chemically modified from its native form.
Cellulose is a linear polymer of β -D-glucopyranose units linked to one another (Kamid, Cellulose And Cellulose Derivatives: Molecular Characterization And Its Applications, Elsevier, 2005). The term "cellulose derivative" refers to cellulose that is chemically modified from the native form. In certain embodiments, the polysaccharide is a cellulose derivative in which one OR more OH groups are substituted by OR, such as Methylcellulose (MC), carboxymethylcellulose (CMC), Hydroxymethylcellulose (HMC), Hydroxypropylcellulose (HPC), Hydroxyethylcellulose (HEC), OR Hydroxypropylmethylcellulose (HPMC), wherein R represents any of a plurality of moieties.
Dextran is a complex branched polysaccharide. Dextran contains multiple glucose moieties linked together by α 1 → 6 glycosidic linkages to form a linear chain. The branches usually start from the α 1 → 3 bond, but they may also start from the α 1 → 2 or α 1 → 4 bond. The term "dextran derivative" refers to dextran that has been chemically modified from the native form. In certain embodiments, the polysaccharide is a dextran derivative in which one OR more OH groups are substituted with OR, wherein R represents any of a plurality of moieties.
Modifications to the polysaccharide may include the addition or creation of new functional groups (e.g., amines, amides, aldehydes, esters, ketones, hydroxyls, hydrazines, hydrazides, maleimides, sulfhydryls, etc.), in which case the polysaccharide is considered to be "functionalized". The proportion of modified sugar subunits can vary, and the degree of modification can be selected to control properties such as gel time, half-life, hardness, and the like. Some modifications retain the native sugar backbone structure, while others open at least some sugar rings. In some embodiments, the polysaccharide derivative is an aldehyde-containing derivative in which the polysaccharide is periodate-treated.
It is understood that in any polysaccharide derivative, only a portion of the sugar moieties in the polysaccharide are modified. The degree of modification may vary. For example, in certain embodiments, 5% to 99% -100% of the relevant sugar moieties (e.g., glucuronic acid moieties in the case of HA) are modified. In certain embodiments, 10% to 75% of the relevant sugar moieties are modified. The degree of modification can be controlled by a variety of methods. For example, the temperature, pH and time at which the reaction is carried out may be varied, and the concentration of a reagent (e.g., carbodiimide, amide, dihydrazide, etc.) may be varied. To achieve a high degree of modification, an excess of modifying agents, such as dihydrazides and/or carbodiimides, may be used. For example, in one embodiment, a 10 to 100 fold excess of the dihydrazide is added to the solution comprising HA, and/or a 2 to 100 fold excess of the carbodiimide reagent is subsequently added to the reaction mixture. In certain embodiments, the values of these parameters are selected to achieve a relatively high degree of modification, e.g., 50% to 99% -100% of the relevant sugar moieties are modified. For example, 50% to 80% of the relevant sugar moieties may be modified. However, the degree of modification is kept low enough that the solution will remain in a proper fluid state without becoming too viscous, thereby facilitating handling and achieving injectability. In certain embodiments, 10% to 30% or 30% to 50% of the relevant sugar moieties are modified.
A variety of polysaccharide derivatives may be used. In certain embodiments, the at least one polysaccharide derivative is a derivative of HA. In certain embodiments, both polysaccharide derivatives are derivatives of HA. In certain embodiments, the matrix forming agent is separated into a first polysaccharide derivative and a second polysaccharide derivative, which upon mixing form a matrix or gel. In some embodiments, the first polysaccharide derivative comprises a first type of crosslinkable functional group and the second polysaccharide derivative comprises a second type of crosslinkable functional group, wherein upon mixing, both types of crosslinkable functional groups form crosslinks between the two polysaccharide derivatives. The polysaccharide derivative may be stored separately as two components of a composition which are mixed during administration, for example during application to the ear canal with a double syringe. In certain embodiments, the polysaccharide is a polysaccharide that is not specifically degraded by human endogenous enzymes.
In certain embodiments, the at least one polysaccharide derivative is a derivative of cellulose. For example, in certain embodiments, the first polysaccharide derivative is a derivative of HA and the second polysaccharide derivative is a derivative of cellulose.
In certain embodiments, the at least one polysaccharide derivative is a derivative of dextran. For example, in certain embodiments, the first polysaccharide derivative is a derivative of HA and the second polysaccharide derivative is a derivative of dextran.
The first and second polysaccharide derivatives comprise a first and second functional group, respectively, which react with each other to form a covalent bond linking the first and second polysaccharide derivatives to each other. The solutions are thus applied as liquids and are brought into contact with one another and optionally mixed together immediately before or at the time of application, or are brought into contact with one another after application. A sufficient number of crosslinks are formed to cause a transition from a liquid to a semi-solid or gel-like state.
In certain embodiments, polysaccharide derivatives are used that comprise at least two different crosslinkable functional groups, wherein the crosslinkable functional groups react with each other to form crosslinks under physiological conditions. The crosslinkable functional groups can be selected such that they do not substantially react with each other prior to exposure to physiological conditions of pH, temperature, and/or salt concentration. It will therefore be appreciated that the matrix former need not be two distinguishable derivatives of HA, but may use a single material comprising a plurality of different functional groups capable of becoming cross-linked.
A variety of different polysaccharide derivatives (e.g., HA derivatives) are used in the composition. In certain embodiments, the first crosslinkable functional group and the second crosslinkable functional group react in sufficient amounts and at a sufficiently fast speed to form a hydrogel a period of time after the solutions are contacted with each other. In certain embodiments, the hydrogel is formed within 1-3 seconds to 5 minutes, 1-3 seconds to 3 minutes, 1-3 seconds to 60 seconds, 1-3 seconds to 30 seconds, or 1-3 seconds to 15 seconds after the solutions are contacted with each other (e.g., after application). Typically, the solutions are mixed together immediately prior to or simultaneously with their administration to the internal body site (e.g., ear canal). For example, solutions may be administered using a multi-barrel injection device (e.g., a multi-barrel syringe), wherein each solution is contained in a separate container or barrel prior to administration. These solutions may be contacted with each other during and/or after application. Preferably, the derivative becomes cross-linked under physiological conditions, for example, in an aqueous environment at a pH of 6.0 to 8.0.
A variety of crosslinkable polysaccharide derivatives and methods of forming them may be used. In certain embodiments, the polysaccharide derivatives become cross-linked to each other without the need for a separate cross-linking agent, e.g., the first and second derivatives comprise functional groups that react with each other to form covalent bonds. In certain embodiments, the polysaccharide derivatives react with each other to produce a non-toxic biocompatible product, such as water. In certain embodiments, both polysaccharide derivatives are not modified by the use of a cross-linking agent. In certain embodiments, the polysaccharide derivative becomes cross-linked without the need for light.
It will be appreciated that in any of the above embodiments, only a portion of the available functional groups on the first and second polysaccharide derivatives will become cross-linked. The crosslinking density can be controlled by, for example, appropriately selecting the molecular weight of the polysaccharide derivative. An exemplary cross-link density is about 1 x 106mol/cm3To about 1X 108mol/cm3. In certain embodiments, the crosslink density is 3X 107mol/cm3To 50X 107mol/cm3。
The polysaccharide derivatives functionalized as described above can be crosslinked by reacting derivatives containing different functional groups with each other. For example, (i) a first polysaccharide derivative comprising an aldehyde can be reacted with a second polysaccharide derivative comprising an amine; (ii) a first polysaccharide derivative comprising an active ester (e.g. NHS ester) may be reacted with a second polysaccharide derivative comprising an amine; (iv) the first polysaccharide derivative comprising a hydrazide can be reacted with a second HA derivative comprising an aldehyde; and so on. In one embodiment of particular interest, the first solution comprises a polysaccharide derivative functionalized with a dihydrazide, and the second solution comprises a polysaccharide that oxidizes to form aldehyde groups (see, e.g., fig. 8).
In certain embodiments, the composition comprises a matrix former comprising a polysaccharide derivative in solution, wherein the concentration of the polysaccharide derivative is greater than 5mg/ml, such as up to 150 mg/ml. In certain embodiments, the concentration of the polysaccharide derivative is greater than 10 mg/ml. In other embodiments, the concentration of the polysaccharide derivative is greater than 15mg/ml, greater than 20mg/ml, or greater than 25 mg/ml. Herein, polysaccharide derivatives of more than 25mg/ml are referred to as "high concentrations". The solution preferably has a sufficiently low viscosity so that it can be easily handled, for example, so that easy injectability exists.
In certain embodiments, the at least one polysaccharide derivative suitable for crosslinking in situ to form a gel comprises a moiety comprising a non-polysaccharide polymer, e.g., the polysaccharide derivative comprises a polysaccharide or derivative thereof covalently linked to one or more non-polysaccharide polymers. By non-polysaccharide is meant that the polymer comprises less than 1% by weight, number, or both of sugar monomers, e.g., the polymer is substantially free of sugar. In certain embodiments, the non-polysaccharide portion comprises from 1% to 10% -90% by weight of the polymer, and/or from 1% to 10% -90% of the monomers are non-saccharide monomers. The attachment can occur anywhere in the polysaccharide chain, for example at either end of the chain or at a location that is internal to the sugar moiety, thereby creating a linear or branched structure. The non-polysaccharide polymer may be any of a variety of polymers, such as any non-polysaccharide polymer that is capable of acting as a hydrogel precursor when covalently linked to a polysaccharide derivative.
In certain embodiments, the matrix-forming agent comprises or consists of a first crosslinkable hydrogel precursor and a second crosslinkable hydrogel precursor, wherein one hydrogel precursor comprises or consists of a polysaccharide derivative, such as HA, cellulose, or dextran derivative, and the other hydrogel precursor comprises or consists of a non-polysaccharide polymer (i.e., less than 1% polymer by weight, or less than 1% of the monomers are sugars). Exemplary non-polysaccharide polymers capable of crosslinking into polysaccharide derivatives to form hydrogels include, but are not limited to: polyethers such as polyethylene glycol (PEG) or polypropylene glycol (PPG), polyethylene oxide (PEO), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polypeptides such as gelatin, chitosan, or poly (1-glutamic acid), and derivatives of any of these, or conjugates, blends or complexes comprising any of these.
Although polysaccharide derivatives are described in detail, in other embodiments, the hydrogel is formed by crosslinking two non-polysaccharide polymers in situ in the adhesion-inhibiting hydrogel. Each non-polysaccharide polymer comprises functional groups, wherein the functional groups are capable of reacting with each other to form covalent bonds. Suitable functional groups are the functional groups described above for crosslinking of the polysaccharide derivative. Exemplary non-polysaccharide polymers include those described above that contain or can be modified to contain functional groups suitable for crosslinking.
Matrix forming agent (and composition thereof)
In one aspect, provided herein is a matrix forming agent described herein. In certain embodiments, the matrix forming agent comprises a polymer. In certain embodiments, the matrix forming agent comprises a polymer gelled by electrostatic interaction. In certain embodiments, the matrix forming agent comprises a polymer that exhibits shear thinning. In certain embodiments, the matrix forming agent comprises a rheological blend of polymers. In certain embodiments, the rheological polymer blend comprises two different polymers, wherein the viscoelastic properties of the rheological polymer blend are more gel-like than the viscoelastic properties of the constituent polymers measured alone. The polymer may be a block copolymer. In certain embodiments, the polymer is not a block copolymer. In certain embodiments, the polymer is a thermosensitive polymer. In certain embodiments, the polymer is poly (N-isopropylacrylamide) (NIPAAm). In certain embodiments, the matrix forming agent or combination of matrix forming agents is not modified by a polyphosphate. In certain embodiments, the matrix forming agent or combination of matrix forming agents is modified by a polyphosphate. In certain embodiments, the matrix forming agent or combination of matrix forming agents comprises a polymer of the formula:
Figure BDA0001614314770000731
Wherein each occurrence of Y is independently-R1or-L2R2；
R1Independently for each occurrence is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2independently for each occurrence is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
R2each occurrence is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -ORb、-N(Rb)2Or an oxygen protecting group;
R3Aindependently for each occurrence is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -ORbor-N (R)b)2；
R of (A) to (B)bIndependently for each occurrence is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group or a nitrogen protecting group, or two R bTogether with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring;
G1Aand G2AEach independently hydrogen, halogen, optionally substituted amine, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroaryl,or an oxygen protecting group; and is
p, q, r, s, and t are each independently integers from 0 to 200, inclusive, where the sum of p and t is at least 1, and the sum of q, r, and s is at least 1.
In certain embodiments, the matrix forming agent or combination of matrix forming agents comprises a polymer of the formula:
Figure BDA0001614314770000741
wherein:
each occurrence of Z is independently-R4；
R4Independently for each occurrence, is optionally substituted alkyl;
G1Aand G2AEach independently hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate or an oxygen protecting group; and is
p, q, r, s and t are each independently integers from 0 to 200, wherein the sum of p and t is at least 1 and the sum of q, r and s is at least 1;
the composition forms a gel at a temperature above the phase transition temperature; and the phase transition temperature is less than about 37 ℃;
And at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) at a temperature of about 37 ℃, the storage modulus of the composition is greater than about 15% of the storage modulus of a reference composition; and
(iii) at a temperature of about 37 ℃, the composition has a loss modulus of about 80% to about 120% of the loss modulus of the reference composition;
wherein the reference composition is a composition in the absence of a penetration enhancer or a combination of penetration enhancers.
In some embodiments, the matrix forming agent comprises a poloxamer. Exemplary embodiments of the inventionPoloxamers include, but are not limited to: poloxamer 407, poloxamer 188, poloxamine, poloxamer 124, poloxamer 237, or poloxamer 338,
Figure BDA0001614314770000742
10R5、
Figure BDA0001614314770000743
17R2、
Figure BDA0001614314770000744
17R4、
Figure BDA0001614314770000745
25R2、
Figure BDA0001614314770000746
25R4、
Figure BDA0001614314770000747
31R1、
Figure BDA0001614314770000748
F108 casting solid surfactant,
Figure BDA0001614314770000749
F 108NF、
Figure BDA00016143147700007410
F 108Pastille、
Figure BDA00016143147700007411
F108 NF Prill poloxamer 338,
Figure BDA00016143147700007412
F 127 NF、
Figure BDA00016143147700007413
F 127 NF 500 BHT Prill、
Figure BDA00016143147700007414
F127 NF Prill poiseLoxam 407, and,
Figure BDA00016143147700007415
F 38、
Figure BDA00016143147700007416
F 38 Pastille、
Figure BDA00016143147700007417
F 68、
Figure BDA00016143147700007418
F 68 LF Pastille、
Figure BDA00016143147700007419
F 68 NF、
Figure BDA00016143147700007420
F68 NF Prill poloxamer 188,
Figure BDA00016143147700007421
F 68 Pastille、
Figure BDA00016143147700007422
F 77、
Figure BDA00016143147700007423
F 77 Micropastille、
Figure BDA0001614314770000751
F 87、
Figure BDA0001614314770000752
F 87 NF、
Figure BDA0001614314770000753
F87 NF Prill poloxamer 237,
Figure BDA0001614314770000754
F 88、
Figure BDA0001614314770000755
F 88 Pastille、
Figure BDA0001614314770000756
FT L 61、
Figure BDA0001614314770000757
L 10、
Figure BDA0001614314770000758
L 101、
Figure BDA0001614314770000759
L 121、
Figure BDA00016143147700007510
L 31、
Figure BDA00016143147700007511
L 35、
Figure BDA00016143147700007512
L 43、
Figure BDA00016143147700007513
L 61、
Figure BDA00016143147700007514
L 62、
Figure BDA00016143147700007515
L 62 LF、
Figure BDA00016143147700007516
L 62D、
Figure BDA00016143147700007517
L 64、
Figure BDA00016143147700007518
L 81、
Figure BDA00016143147700007519
L 92、
Figure BDA00016143147700007520
L44 NF INH surfactant poloxamer 124,
Figure BDA00016143147700007521
N 3、
Figure BDA00016143147700007522
P 103、
Figure BDA00016143147700007523
P 104、
Figure BDA00016143147700007524
P 105、
Figure BDA00016143147700007525
P123 surfactant,
Figure BDA00016143147700007526
P 65、
Figure BDA00016143147700007527
P 84、
Figure BDA00016143147700007528
P 85、
Figure BDA00016143147700007529
PE/F 108、
Figure BDA00016143147700007530
PE/P105、
Figure BDA00016143147700007531
PE/P84、
Figure BDA00016143147700007532
PE/L31、
Figure BDA00016143147700007533
PE/L61、
Figure BDA00016143147700007534
PE/L101、
Figure BDA00016143147700007535
PE/L121、
Figure BDA00016143147700007536
PE/L42、
Figure BDA00016143147700007537
PE/L62、
Figure BDA00016143147700007538
PE/L92、
Figure BDA00016143147700007539
PE/L44、
Figure BDA00016143147700007540
PE/L64、
Figure BDA00016143147700007541
PE/P84、
Figure BDA00016143147700007542
PE/P75、
Figure BDA00016143147700007543
PE/P103、
Figure BDA00016143147700007544
PE/F87、
Figure BDA00016143147700007545
PE/F127、
Figure BDA00016143147700007546
PE/F38、
Figure BDA00016143147700007547
PE/F68、
Figure BDA00016143147700007548
P 188、
Figure BDA00016143147700007549
P 407、
Figure BDA00016143147700007550
P 188micro、
Figure BDA00016143147700007551
P 407micro、
Figure BDA00016143147700007552
P237、
Figure BDA00016143147700007553
P 338、
Figure BDA00016143147700007554
EL、
Figure BDA00016143147700007555
HS 15、
Figure BDA00016143147700007556
PS 80、
Figure BDA00016143147700007557
PS 60、
Figure BDA00016143147700007558
RH 40、
Figure BDA00016143147700007559
TPG S、
Figure BDA00016143147700007560
CS L、
Figure BDA00016143147700007561
CS A、
Figure BDA00016143147700007562
CS S、
Figure BDA00016143147700007563
CS B、
Figure BDA00016143147700007564
CS 20 and
Figure BDA00016143147700007565
and (3) a CS 12. In some embodiments, the matrix forming agent comprises any one of the foregoing poloxamers, derivatives thereof, or block copolymers thereof.
In certain embodiments, the matrix forming agent comprises poloxamer 407, poloxamer 188, poloxamine, poloxamer 124, poloxamer 237 or poloxamer 338. In certain embodiments, the block copolymer comprises poloxamer 407. In certain embodiments, the matrix forming agent comprises a poloxamer with polyphosphate monomers. In certain embodiments, the matrix forming agent comprises poloxamer 407 with polyphosphate monomers. In certain embodiments, the matrix forming agent or combination of matrix forming agents comprises a polymer of the formula:
Figure BDA00016143147700007566
wherein:
each occurrence of Z is independently-R4；
R4Each occurrence is independently optionally substituted alkyl;
G1Aand G2AEach independently is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate or an oxygen protecting group; and is
p and t are each independently an integer from 0 to 200, inclusive, wherein the sum of p and t is at least 1;
the composition forms a gel at a temperature above the phase transition temperature; and the phase transition temperature is less than about 37 ℃;
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus about 5 ℃;
(ii) At a temperature of about 37 ℃, the storage modulus of the composition is greater than about 15% of the storage modulus of a reference composition; and
(iii) at a temperature of about 37 ℃, the composition has a loss modulus of about 80% to about 120% of the loss modulus of the reference composition;
wherein the reference composition is a composition in the absence of a penetration enhancer or a combination of penetration enhancers.
The polymer of formula (I') comprises R3A. In certain embodiments, each R is3AAre the same substituents. In certain embodiments, each R in the polymer3AIs one of two specific substituents. In certain embodiments, each R in the polymer3AIs one of three specific substituents. In certain embodiments, each R in the polymer3AIs one of four specific substituents. In certain embodiments, each R in the polymer3AIs one of five specific substituents. In certain embodiments, each R in the polymer3AIs one of six specific substituents. In certain embodiments, each R in the polymer3AIs one of seven or more specific substituents.
As generally described herein, R3AIndependently for each occurrence, is optionally hydrogen, substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR bor-N (R)b)2. In certain embodiments, R3AEach occurrence is independently unsubstituted alkyl.
In certain embodiments, R3AIs hydrogen. In certain embodiments, R3AIs optionally substituted alkyl, e.g. optionally substituted C1-6Alkyl, optionally substituted C1-2Alkyl, optionally substituted C2-3Alkyl, optionally substituted C3-4Alkyl, optionally substitutedC4-5Alkyl or optionally substituted C5-6An alkyl group. In certain embodiments, R3AIs unsubstituted alkyl, e.g. unsubstituted C1-6Alkyl, unsubstituted C1-2Alkyl, unsubstituted C2-3Alkyl, unsubstituted C3-4Alkyl, unsubstituted C4-5Alkyl or unsubstituted C5-6An alkyl group. In certain embodiments, R3AIs unsubstituted C1-20An alkyl group. In certain embodiments, R3AIs unsubstituted C1-12An alkyl group. In certain embodiments, R3AIs methyl. In certain embodiments, R3AIs ethyl, propyl or butyl. In certain embodiments, R3AIs haloalkyl, e.g., -CHF2、-CHCl2、-CH2CHF2、-CH2CHCl2. In certain embodiments, R3AIs perhaloalkyl, e.g., -CF3、-CF2CF3、-CCl3. In certain embodiments, R3AIs hydroxyalkyl, e.g., -CH2OH、-CH2CH2OH、-CH2ORb、-CH2CH2ORb. In certain embodiments, R3AIs aminoalkyl, e.g., -CH2NH2、-CH2CH2NH2、-CH2NMe2、-CH2CH2NMe2、-CH2N(Rb)2、-CH2CH2N(Rb)2。
In certain embodiments, R 3AIs optionally substituted alkenyl, e.g. optionally substituted C2-6An alkenyl group. In certain embodiments, R3ABeing unsubstituted alkenyl, e.g. unsubstituted C2-6An alkenyl group. In certain embodiments, R3AIs vinyl, allyl or isoprenyl. In certain embodiments, R3AIs optionally substituted alkynyl, e.g. optionally substituted C2-6Alkynyl. In certain embodiments, R3AIs unsubstituted alkynyl, e.g. unsubstituted C2-6Alkynyl.
In certain embodiments, R3AIs an optionally substituted aryl group, for example, an optionally substituted phenyl group. In certain embodiments, R3AIs an unsubstituted aryl group, for example, an unsubstituted phenyl group. In certain embodiments, R3AIs an optionally substituted heteroaryl group, for example, an optionally substituted 5-to 6-membered heteroaryl group or an optionally substituted 9-to 10-membered bicyclic heteroaryl group. In certain embodiments, R3AIs an unsubstituted heteroaryl, e.g., an unsubstituted 5-to 6-membered heteroaryl or an unsubstituted 9-10 membered bicyclic heteroaryl.
In certain embodiments, R3AIs optionally substituted acyl, e.g., -CHO, -CO2H or-C (═ O) NH2. In certain embodiments, R3AIs an optionally substituted carbonyl group. In certain embodiments, R 3Ais-C (═ O) Rb、-C(＝O)ORb、-C(＝O)NH(Rb) or-C (═ O) N (R)b)2. In certain embodiments, R3Ais-C (═ O) RbAnd R isbIs an optionally substituted alkyl group, for example, -C (═ O) Me. In certain embodiments, R3is-C (═ O) RbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3Ais-C (═ O) RbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R3Ais-C (═ O) ORbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R3Ais-C (═ O) ORbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3Ais-C (═ O) ORbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R3Ais-C (═ O) N (R)b)2And at least one RbIs an optionally substituted alkyl group. In certain embodiments, R3is-C (═ O) NHRbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R3Ais-C (═ O) NHRbAnd R isbIs optionally selected fromA substituted alkenyl group. In certain embodiments, R3Ais-C (═ O) NHRbAnd R isbIs an optionally substituted carbocyclyl, heterocyclyl, aryl or heteroaryl group. In certain embodiments, R3AIs optionally substituted vinylcarbonyl (e.g., -C (═ O) CH ═ CH 2、-C(＝O)CMe＝CH2)。
In certain embodiments, R3Ais-ORbFor example, -OH. In certain embodiments, R3Ais-ORbAnd R isbIs an optionally substituted alkyl group. In certain embodiments, R3Ais-ORbAnd R isbIs unsubstituted C1-6An alkyl group. In certain embodiments, R3Ais-ORbAnd R isbIs an optionally substituted alkenyl group. In certain embodiments, R3Ais-ORbAnd R isbIs optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl. In certain embodiments, R3Ais-ORbAnd R isbUnsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl. In certain embodiments, R3Ais-ORbAnd R isbIs optionally substituted acyl, e.g. R3Ais-OC (═ O) Rb、-OC(＝O)ORbor-OC (═ O) N (R)b)2. In certain embodiments, R3Ais-ORbAnd R isbIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl).
In certain embodiments, R3Ais-N (R)b)2E.g., -NH2、-NHRb. In certain embodiments, R3Ais-NH (R)b) And R isbIs an optionally substituted alkyl group. In certain embodiments, R 3is-N (R)b)2And at least one RbIs an optionally substituted alkyl group. In certain embodiments, R3Ais-NH (R)b) And R isbIs an unsubstituted alkyl group. In certain embodiments, R3Ais-N (R)b)2And at least one RbIs an unsubstituted alkyl group. In certain embodiments, R3Ais-NHRbAnd R isbIs optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R3Ais-NHRbAnd R isbIs unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl or unsubstituted heteroaryl. In certain embodiments, R3Ais-NHRbAnd R isbIs optionally substituted acyl, e.g. R3Ais-NHC (═ O) Rb、-NHC(＝O)ORbor-NHC (═ O) NHRb. In certain embodiments, R3Ais-N (R)b)2And at least one RbIs a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts). In certain embodiments, R3Ais-N (R)b)2And two R arebLinked to form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring. In certain embodiments, R3Ais-N (R)b)2And two RbAre linked to form an unsubstituted heterocyclic ring or an unsubstituted heteroaryl ring.
In some embodiments, G1AAnd G2AThe same is true. In some embodiments, G1AAnd G2ADifferent. In certain embodiments, G1AIs hydrogen. In certain embodiments, G1AIs an optionally substituted alkyl group. In certain embodiments, G1AIs an optionally substituted acyl group. In certain embodiments, G1AIs an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G1AIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, ethanAcyl, pivaloyl, benzoyl). In certain embodiments, G1AIs hydrogen. In certain embodiments, G1AIs an optionally substituted alkyl group. In certain embodiments, G1AIs an optionally substituted acyl group. In certain embodiments, G1AIs an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G1AIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G 1AIs an optionally substituted aryl group, for example, an optionally substituted phenyl group. In certain embodiments, G1AIs an unsubstituted aryl group, for example, an unsubstituted phenyl group. In certain embodiments, G1AIs an optionally substituted heteroaryl group, for example, an optionally substituted 5-to 6-membered heteroaryl group or an optionally substituted 9-to 10-membered bicyclic heteroaryl group. In certain embodiments, G1AIs an unsubstituted heteroaryl, e.g., an unsubstituted 5-to 6-membered heteroaryl or an unsubstituted 9-to 10-membered bicyclic heteroaryl.
In certain embodiments, G2AIs hydrogen. In certain embodiments, G2AIs optionally substituted alkyl. In certain embodiments, G2AIs an optionally substituted acyl group. In certain embodiments, G2AIs an optionally substituted phosphate (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G2AIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G2Is hydrogen. In certain embodiments, G2AIs an optionally substituted alkyl group. In certain embodiments, G 2Is an optionally substituted acyl group. In certain embodiments, G2AIs optionally substituted phosphorusAcid esters (e.g., -P (═ O) (OH)2-P (═ O) (O-alkyl)2P (═ O) (OH) (O-alkyl), — P (═ O) (OH) (O-Y), — P (═ O) (O-alkyl) (O-Y). In certain embodiments, G2AIs an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, benzoyl). In certain embodiments, G2AIs an optionally substituted aryl group, for example, an optionally substituted phenyl group. In certain embodiments, G2AIs an unsubstituted aryl group, for example, an unsubstituted phenyl group. In certain embodiments, G2AIs an optionally substituted heteroaryl group, for example, an optionally substituted 5-to 6-membered heteroaryl group or an optionally substituted 9-to 10-membered bicyclic heteroaryl group. In certain embodiments, G2AIs an unsubstituted heteroaryl, e.g., an unsubstituted 5-6 membered heteroaryl or an unsubstituted 9-to 10-membered bicyclic heteroaryl. In certain embodiments, G1AAnd G2AAre all hydrogen.
In certain embodiments, each occurrence of Z is independently-R4. As generally described herein, R4Each occurrence is independently optionally substituted alkyl. In certain embodiments, R 4Is optionally substituted alkyl, e.g. optionally substituted C1-6Alkyl, optionally substituted C1-2Alkyl, optionally substituted C2-3Alkyl, optionally substituted C3-4Alkyl, optionally substituted C4-5Alkyl or optionally substituted C5-6An alkyl group. In certain embodiments, R4Is unsubstituted alkyl, e.g. unsubstituted C1-6Alkyl, unsubstituted C1-2Alkyl, unsubstituted C2-3Alkyl, unsubstituted C3-4Alkyl, unsubstituted C4-5Alkyl or unsubstituted C5-6An alkyl group. In certain embodiments, R4Is unsubstituted C1-20An alkyl group. In certain embodiments, R4Is unsubstituted C1-12An alkyl group. In certain embodiments, R4Is methyl. In certain embodiments, R4Is ethyl, propyl or butyl. In certain embodiments, R4Is ethyl. In some casesIn embodiments, R4Is propyl. In certain embodiments, R4Is butyl. In certain embodiments, R4Is n-butyl. In certain embodiments, R4Is sec-butyl. In certain embodiments, R4Is of the formula:
Figure BDA0001614314770000801
wherein n is independently at each occurrence an integer from 0 to 20, inclusive.
In certain embodiments, R4Is of the formula:
Figure BDA0001614314770000802
wherein n is independently at each occurrence an integer from 0 to 20, inclusive. In certain embodiments, R 4Is of the formula:
Figure BDA0001614314770000803
in certain embodiments, R4Is of the formula:
Figure BDA0001614314770000804
in certain embodiments, R4Is of the formula:
Figure BDA0001614314770000805
in certain embodiments, R4Is of the formula:
Figure BDA0001614314770000806
in certain embodiments, p is 0. In certain embodiments, p is an integer from 1 to 100, inclusive. In some embodiments, p is an integer from 10 to 100, inclusive. In some embodiments, p is an integer from 10 to 50, inclusive. In some embodiments, p is an integer from 10 to 25, inclusive. In some embodiments, p is an integer from 1 to 10, inclusive. In certain embodiments, p is 5.
In certain embodiments, t is 0. In certain embodiments, t is an integer from 1 to 100, inclusive. In some embodiments, t is an integer from 10 to 100, inclusive. In some embodiments, t is an integer from 10 to 50, inclusive. In some embodiments, t is an integer from 10 to 25, inclusive. In some embodiments, t is an integer from 1 to 10, inclusive. In certain embodiments, t is 5. In certain embodiments, p is 5 and t is 5.
In certain embodiments, the polymer is of the formula:
Figure BDA0001614314770000811
In certain embodiments, the matrix forming agent or combination of matrix forming agents comprises a polymer of formula (Γ) as part of a composition. In certain embodiments, the matrix forming agent or combination of matrix forming agents comprises a polymer of formula (IA) as part of the composition. In certain embodiments, the matrix forming agent or combination of matrix forming agents comprises a polymer of formula (II) as part of a composition.
Methods of treatment and uses
Methods of using the various embodiments of the compositions described herein generally relate to methods of treating infectious diseases or otic disorders. In certain embodiments, the compositions described herein are used in methods of treating infectious diseases. In certain embodiments, the matrix-forming agents described herein are used in methods of treating an infectious disease. In certain embodiments, the compositions described herein are used in methods of treating otic disorders. In certain embodiments, the compositions described herein are used in methods of treating infectious otic disorders. Methods of using the various embodiments of the compositions described herein generally relate to methods of treating infectious diseases. In various aspects, the compositions can be used to deliver therapeutic or diagnostic agents across the tympanic membrane. Thus, the compositions are particularly useful for treating middle and/or inner ear diseases. In certain embodiments, the compositions described herein are used in methods of treating a middle ear disease. In certain embodiments, the compositions described herein are used in methods of treating inner ear diseases.
In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
In various aspects, the compositions described herein can be used to treat otic disorders, including but not limited to otic infections, the development of fibroids in the middle ear, or otosclerosis. In certain embodiments, the matrix-forming agents described herein are useful for treating otic disorders, including but not limited to otic infections, development of fibroids in the middle ear, or otosclerosis. In various other aspects, the compositions described herein can be used to treat vertigo, Meniere's disease, mastoiditis, cholesteatoma, labyrinthitis, perilymphatic fistula, superior semicircular canal tear syndrome, otorrhea, otodynia, tinnitus, barotrauma, otic cancer, autoimmune inner ear disease acoustic neuroma, benign paroxysmal positional vertigo, herpes zoster of the ears, purulent labyrinthitis, vestibular neuronitis, tympanic membrane perforation or myringitis. In various other aspects, the compositions described herein can be used to treat vertigo, meniere's disease, mastoiditis, cholesteatoma, labyrinthitis, perilymphatic fistula, superior semicircular canal tear syndrome, otorrhea, ear pain, tinnitus, barotrauma, ear cancer, autoimmune inner ear disorders auditory neuroma, benign paroxysmal positional vertigo, herpes zoster of the ear, purulent labyrinthitis, vestibular neuronitis, tympanic membrane perforation or myringitis. In certain embodiments, the matrix forming agents described herein can be used to treat vertigo, meniere's disease, mastoiditis, cholesteatoma, labyrinthitis, perilymphatic fistula, superior semicircular canal syndrome, otorrhea, ear pain, tinnitus, barotrauma, ear cancer, autoimmune inner ear disorders auditory neuroma, benign paroxysmal positional vertigo, herpes zoster of the ear, purulent labyrinthitis, vestibular neuronitis, tympanic membrane perforation or myringitis. In some embodiments, the methods disclosed herein are used to treat Otitis Media (OM). Different forms of OM that can be treated by the methods disclosed herein can be distinguished by the presence of fluid (exudate) and/or the duration or persistence of inflammation. In certain embodiments, the infectious disease is acute otitis media, chronic otitis media, or secretory otitis media. Exudate, if present, may be any consistency from aqueous (serous) to viscous mucoid (mucoid) to pus (purulent); duration is classified as acute, subacute or chronic. Om (ome) with exudate indicates inflammation with Middle Ear Fluid (MEF), but without any signs of acute infection. Acute OM (AOM), with or without exudate, is characterized by rapid onset of signs and symptoms associated with Acute infections in the middle ear (e.g., earache, fever). In some embodiments, the methods are used to treat otitis media associated with infection by any of a number of pathogenic bacteria including, for example, Streptococcus pneumoniae, Haemophilus influenzae (Haemophilus influenzae), and Moraxella catarrhalis (Moraxella catarrhalis).
The infectious disease may be a bacterial infection. In certain embodiments, the bacterial infection is a streptococcal (Streptococcus), Haemophilus (Haemophilus) or Moraxella (Moraxella) infection. In certain embodiments, the bacterial infection is a staphylococcal (Staphylococcus), Escherichia (Escherichia), or Bacillus (Bacillus) infection. In certain embodiments, the bacterial infection is a haemophilus influenzae infection. In certain embodiments, the bacterial infection is a streptococcus pneumoniae infection. In certain embodiments, the bacterial infection is a moraxella catarrhalis infection. In certain embodiments, the infectious disease is an ear infection. In certain embodiments, the infectious disease is otitis media.
In various embodiments, administration of the compositions of the present invention consists of applying the composition into the ear canal of the subject. In certain embodiments, applying the composition to the ear canal of the subject comprises spraying the composition into the ear canal of the subject. In certain embodiments, administration of a composition of the invention consists of applying the composition to the inner ear of a subject. In certain embodiments, administration of a composition of the invention consists of applying the composition to the middle ear of a subject. In certain embodiments, administration of a composition of the invention consists of applying the composition into the inner ear, sinus, eye, vagina or skin of a subject. In certain embodiments, administration of a composition of the invention consists of administering the composition into the nasal sinuses of a subject. In certain embodiments, administration of a composition of the invention consists of applying the composition to the eye of a subject. In certain embodiments, administration of the compositions of the present invention consists of applying the compositions into the vagina of a subject. In certain embodiments, application of the compositions of the present invention consists of applying the composition to the skin of a subject. The subject may be any mammal in need of treatment. In various aspects, the composition is in direct contact with the tympanic membrane for about 1 day to about 30 days. In various aspects, the composition is contacted with the tympanic membrane for about 1 day to about 3 days, about 3 days to about 7 days, about 7 days to about 14 days, about 14 days to about 21 days, or about 21 days to about 30 days. In various embodiments, the composition forms a sustained release reservoir in contact with the tympanic membrane. In various aspects, the composition is applied as a liquid into the ear canal and the composition gels in situ on the tympanic membrane surface. When in contact with the tympanic membrane, the therapeutic agent penetrates the tympanic membrane and is delivered to the middle ear. In various embodiments, delivery across the tympanic membrane is a sustained release of the therapeutic agent for a plurality of days. The number of days the composition may be in contact with the tympanic membrane may be, but is not limited to, 5 days, 7 days, 10 days, 14 days, 21 days, or 30 days. The composition may be applied singly or repeatedly during the course of treatment. In various aspects, the composition can be administered periodically from about every 1 day to about every 7 days, from about every 1 day to about every 14 days, or from about every 1 day to about every 30 days. In various embodiments, the composition is naturally excreted from the subject at the end of the treatment by a natural process similar to the excretion of cerumen (ear wax). In certain embodiments, the composition may decompose naturally, and its degradation products may be eliminated by the subject. In various embodiments, administration of the compositions of the present invention comprises adding a matrix forming agent, a penetration enhancer, and a therapeutic agent to the ear canal; then adding a second therapeutic agent to the ear canal; and mixing the matrix forming agent, the penetration enhancer, and the therapeutic agent over the ear canal. In certain embodiments, the second therapeutic agent is an anesthetic. In certain embodiments, the second therapeutic agent is a local anesthetic.
In various embodiments, administration of the compositions of the present invention comprises adding a matrix forming agent to the ear canal; adding a penetration enhancer to the ear canal; adding a therapeutic agent to the ear canal; and mixing the matrix forming agent, the penetration enhancer, and the therapeutic agent over the ear canal. In various embodiments, administration of the compositions of the present invention comprises adding a matrix forming agent to the ear canal; adding a penetration enhancer to the ear canal; adding a therapeutic agent to the ear canal; adding an additional therapeutic agent to the ear canal; and mixing the matrix forming agent, the penetration enhancer, and the therapeutic agent over the ear canal. In certain embodiments, adding the therapeutic agent to the ear canal and adding the penetration enhancer to the ear canal includes spraying the therapeutic agent and spraying the penetration enhancer into the ear canal.
In various embodiments, administration of the compositions of the present invention comprises adding a therapeutic agent to the ear canal; adding a penetration enhancer to the ear canal; adding a matrix forming agent to the ear canal; and mixing the matrix forming agent, the penetration enhancer, and the therapeutic agent over the ear canal. In various embodiments, administration of the compositions of the present invention comprises adding a therapeutic agent to the ear canal; adding an additional therapeutic agent to the ear canal; adding a penetration enhancer to the ear canal; adding a matrix forming agent to the ear canal; and mixing the matrix forming agent, the penetration enhancer, and the therapeutic agent over the ear canal. In certain embodiments, adding the therapeutic agent to the ear canal and adding the penetration enhancer to the ear canal includes spraying the therapeutic agent and spraying the penetration enhancer into the ear canal. In certain embodiments, the therapeutic agent is an antibiotic or an anesthetic. In certain embodiments, the therapeutic agent is an antibiotic. In certain embodiments, the therapeutic agent is an anesthetic. In certain embodiments, the penetration enhancer is bupivacaine.
In various embodiments, administration of the compositions of the present invention comprises adding a composition comprising one or more therapeutic agents, one or more penetration enhancers, and one or more matrix forming agents to the ear canal; a composition that does not contain a therapeutic agent or contains one or more therapeutic agents, does not contain a penetration enhancer or contains one or more penetration enhancers and does not contain a matrix forming agent or contains one or more matrix forming agents is then added to the ear canal. In certain embodiments, the subsequent addition of one or more therapeutic agents includes the same therapeutic agent as the first addition of one or more therapeutic agents. In certain embodiments, the subsequent addition of one or more therapeutic agents includes a different therapeutic agent than the first addition of one or more therapeutic agents. In certain embodiments, the subsequent addition of the permeation enhancer includes the same permeation enhancer as the first addition of the permeation enhancer. In certain embodiments, the subsequent addition of the permeation enhancer includes a different permeation enhancer than the first addition of the permeation enhancer. In certain embodiments, the subsequent addition of a matrix-forming agent comprises the same matrix-forming agent as the first addition of the matrix-forming agent. In certain embodiments, the subsequent addition of a matrix-forming agent comprises a different matrix-forming agent than the first addition of the matrix-forming agent. In certain embodiments, the time interval between the addition of the first composition and the second composition is about 1 minute. In certain embodiments, the time interval between the addition of the first composition and the second composition is less than 1 minute. In certain embodiments, the time interval between the addition of the first composition and the second composition is greater than 1 minute.
The dose is determined based on the minimum inhibitory concentration required at the site of infection. Without being bound by a particular theory, in various aspects, the minimum inhibitory concentration for ciprofloxacin, haemophilus influenzae or streptococcus pneumoniae middle ear infection is about 4 μ g/mL. In various aspects, a typical dose would require about 12 μ g ciprofloxacin based on a mean middle ear volume of 3 mL. In various embodiments, the composition will comprise a sufficient dose to deliver 12 μ g of ciprofloxacin to the middle ear. In various aspects, administration of the composition comprises a single application. In other aspects, the application of the composition comprises multiple applications. For example, the composition may be administered two, three, four or more times. In certain embodiments, the administration of the composition is repeated until a desired clinical result is achieved. For example, infections are resolved. In certain embodiments, the administration of the composition comprises a first administration of the composition followed by a second administration of the composition after a period of time. In certain embodiments, the period of time between the first administration of the composition and the second administration of the composition is one week. In certain embodiments, the time period between the first administration of the composition and the second administration of the composition is greater than one week. In certain embodiments, the period of time between the first administration of the composition and the second administration of the composition is one month. In certain embodiments, the time period between the first administration of the composition and the second administration of the composition is greater than one month. In various embodiments, administration of the compositions of the present invention comprises first administering the composition without a local anesthetic to the ear canal; the composition without the local anesthetic is then administered a second time to the ear canal. In certain embodiments, administration of a composition of the invention comprises first administering a composition having a local anesthetic to the ear canal; the composition without the local anesthetic is then administered a second time to the ear canal.
In various embodiments, administration of the compositions of the present invention comprises first administering the composition without a local anesthetic to the ear canal; a composition without a penetration enhancer other than a local anesthetic is then administered a second time to the ear canal. In certain embodiments, administration of a composition of the invention comprises first administering a composition having a local anesthetic to the ear canal; a composition without a penetration enhancer other than a local anesthetic is then administered a second time to the ear canal. In certain embodiments, the composition of the first administration and the composition of the second administration are the same. In certain embodiments, the composition administered at the first time is different from the composition administered at the second time.
Provided herein are methods of delivering a composition of the present disclosure to a surface of a tympanic membrane of a subject. In certain embodiments, the subject has an otic disorder. In some embodiments, the subject has otitis media. In some embodiments, the subject is a human. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
In certain embodiments, the method of delivery comprises administering the composition into the ear canal via an applicator. In certain embodiments, the method of delivery comprises placing drops (drop) of the composition into the ear canal. In some embodiments, the drops are delivered from a dropper (e.g., pipette, eye dropper). In some embodiments, the drops are delivered by a syringe. The syringe may be connected to a needle, a rigid catheter or a flexible catheter.
In certain embodiments, the method of delivery comprises placing a dose of the composition into the ear canal using a catheter. In some embodiments, the catheter is connected to a syringe. In some embodiments, the catheter is rigid. In some embodiments, the catheter is flexible. In certain embodiments, the method of delivery comprises placing a dose of the composition into the ear canal using a needle. In some embodiments, the needle is connected to a syringe. In some embodiments, the needle has a blunt tip.
In certain embodiments, the method of delivery comprises placing a dose of the composition into the ear canal using a dual barrel syringe. A dual barrel syringe may be used to hold the two components of the composition until mixing of the two components occurs during administration (e.g., in situ). In some embodiments, the dual barrel syringe is connected to a single catheter or needle. In some embodiments, each barrel of a dual barrel syringe is connected to a separate needle or catheter.
In certain embodiments, a method of treating an infectious disease or a disease of the both ears comprises instructing a subject to administer a composition to the subject or providing instructions to the subject for self-administration of the composition.
In another aspect, provided herein is a method of eradicating a biofilm in a subject comprising administering to a subject in need thereof a composition described herein. In another aspect, provided herein is a method of eradicating a biofilm comprising contacting the biofilm with a composition described herein.
In another aspect, provided herein is a method of inhibiting biofilm formation in a subject, comprising administering to a subject in need thereof a composition described herein. In another aspect, provided herein is a method of inhibiting biofilm formation comprising contacting a surface with a composition described herein.
Medicine box
Provided herein are kits comprising any of the compositions described herein, which may additionally comprise a sterile packaged composition. Provided herein is a kit comprising any of the compositions or matrix-forming agents described herein, which may additionally comprise a sterile-packaged composition or matrix-forming agent. The kit may comprise two containers for the two-part matrix-forming agent. The therapeutic agent may be contained in one or both containers of the matrix-forming agent, or the therapeutic agent may be packaged separately. The permeation enhancer may be contained in one or both containers of the matrix forming agent, or the permeation enhancer may be packaged separately. In various aspects, the kit may comprise bottles, and a dropper or syringe for each bottle.
In certain embodiments, the kit comprises one or more droppers (e.g., pipettes, eye droppers). In certain embodiments, the kit comprises one or more syringes. In some embodiments, the syringe is pre-loaded with the composition or one or more components of the composition. In certain embodiments, the kit comprises one or more needles (e.g., blunt-ended needles). In certain embodiments, the kit comprises one or more catheters (e.g., flexible catheters).
In some cases, the kit comprises a dual syringe. In some embodiments, the dual barrel syringe is pre-loaded with two components of the composition. In some embodiments, the dual barrel syringe is connected to a single catheter or needle. In some embodiments, each barrel of a dual barrel syringe is connected to a separate needle or catheter.
In certain embodiments, the kits described herein further comprise instructions for using the kit, e.g., instructions for using the kit in methods of the disclosure (e.g., instructions for administering a compound or pharmaceutical composition described herein to a subject). The kits described herein may also contain information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA).
Definition of
Chemical definition
The definitions of specific functional groups and chemical terms are described in more detail below. According to the CAS version of the Periodic Table of the Elements of the inner cover of the 75 th edition of the Handbook of Chemistry and Physics (CAS version, Handbook of Chemistry and Physics, 75)thEd, inside cover) identifies the chemical element, the specific functional group being generally as defined therein. Furthermore, the general principles of organic chemistry as well as specific functional moieties and reactivity are described in the following: organic Chemistry, Thomas Sorrell, University Science Books, Sausaltio, 1999; smith and March March's Advanced Organic Chemistry, 5 th edition, John Wiley &Sons, inc., New York, 2001; larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and carrousers, Some Modem Methods of Organic Synthesis, 3 rd edition, Cambridge University Press, Cambridge, 1987.
The compounds described herein may contain one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms (e.g., enantiomers and/or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al, eneriomers, Racemates and solutions (Wiley Interscience, New York, 1981); wilen et al, Tetrahedron 33: 2725 (1977); eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H.tables of solving Agents and Optical solutions, page 268 (E.L.Eliel, eds., Univ.of Notre Dame Press, Notre Dame, IN 1972). The invention also includes the compound as an individual isomer substantially free of other isomers, or as a mixture of isomers.
Unless otherwise indicated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, instead of hydrogen by deuterium or tritium, by18F replacement19F, or by13C or14C replacement12In addition to C, compounds having the structure of the present invention are also within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in bioassays.
When a range of values is recited, it is intended to include each value and subrange within the range. For example, "C1-6Alkyl is intended to include C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5And C5-6An alkyl group.
The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 10 carbon atoms ("C1-10Alkyl "). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C)1-9Alkyl "). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C)1-8Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C)1-7Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C) 1-6Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C)1-5Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C)1-4Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C)1-3Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C)1-2Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C)1Alkyl "). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C)2-6Alkyl "). C1-6Examples of alkyl groups include methyl (C)1) Ethyl (C)2) Propyl group (C)3) (e.g., n-propyl, isopropyl), butyl (C)4) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C)5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C)6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C)7) N-octyl (C)8) And the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halo, such as F). In certain embodiments, alkyl is unsubstituted C 1-10Alkyl (e.g. unsubstituted C)1-6Alkyl radicals, e.g. -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted t-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, alkyl is substituted C1-10Alkyl (e.g. substituted C)1-6Alkyl radicals, e.g. CF3、Bn)。
The term "haloalkyl" is a substituted alkyl group wherein one or more hydrogen atoms are independently replaced by a halogen such as fluorine, bromine, chlorine or iodine. In some embodiments, haloalkyl moieties have 1 to 8 carbon atoms ("C1-8Haloalkyl "). In some embodiments, haloalkyl moieties have 1 to 6 carbon atoms ("C1-6Haloalkyl "). In some embodiments, haloThe alkyl moiety having from 1 to 4 carbon atoms ("C)1-4Haloalkyl "). In some embodiments, haloalkyl moieties have 1 to 3 carbon atoms ("C1-3Haloalkyl "). In some embodiments, haloalkyl moieties have 1 to 2 carbon atoms ("C1-2Haloalkyl "). Examples of haloalkyl groups include-CHF 2、-CH2F、-CF3、-CH2CF3、-CF2CF3、-CF2CF2CF3、-CCl3、-CFCl2、-CF2Cl, and the like.
The term "heteroalkyl" refers to an alkyl group that also contains at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (parent chain) and/or at one or more terminal positions. In certain embodiments, heteroalkyl refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc1-10Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc1-9Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc1-8Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc1-7Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroc1-6Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroc 1-5Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroc1-4Alkyl "). In some embodiments, heteroalkyl is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroc)1-3Alkyl "). In some embodiments, heteroalkyl is with 1 to 2 carbon atoms in the parent chainAnd a saturated group of 1 heteroatom ('HetC')1-2Alkyl "). In some embodiments, heteroalkyl refers to a saturated group having 1 carbon atom and 1 heteroatom ("heteroc1Alkyl "). In some embodiments, heteroalkyl is a saturated group having from 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroc2-6Alkyl "). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl is unsubstituted heteroc1-10An alkyl group. In certain embodiments, heteroalkyl is substituted heteroC1-10An alkyl group.
The term "alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, alkenyl groups have 2 to 9 carbon atoms ("C) 2-9Alkenyl "). In some embodiments, alkenyl groups have 2 to 8 carbon atoms ("C)2-8Alkenyl "). In some embodiments, alkenyl groups have 2 to 7 carbon atoms ("C)2-7Alkenyl "). In some embodiments, alkenyl groups have 2 to 6 carbon atoms ("C)2-6Alkenyl "). In some embodiments, alkenyl groups have 2 to 5 carbon atoms ("C)2-5Alkenyl "). In some embodiments, alkenyl groups have 2 to 4 carbon atoms ("C)2-4Alkenyl "). In some embodiments, alkenyl groups have 2 to 3 carbon atoms ("C)2-3Alkenyl "). In some embodiments, alkenyl has 2 carbon atoms ("C)2Alkenyl "). One or more carbon-carbon double bonds may be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). C2-4Examples of the alkenyl group include vinyl (C)2) 1-propenyl (C)3) 2-propenyl group (C)3) 1-butenyl (C)4) 2-butenyl (C)4) Butadienyl radical (C)4) And the like. C2-6Examples of the alkenyl group include the above-mentioned C2-4Alkenyl and pentenyl (C)5) Pentadienyl (C)5) Hexenyl (C)6) And the like. Additional examples of alkenyl groups include hepteneRadical (C)7) Octenyl (C)8) Octrienyl (C)8) And the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, alkenyl is unsubstituted C 2-10An alkenyl group. In certain embodiments, alkenyl is substituted C2-10An alkenyl group. In the alkenyl group, a stereochemical C ═ C double bond (e.g., -CH ═ CHCH)3Or
Figure BDA0001614314770000901
) May be an (E) -or (Z) -double bond.
The term "heteroalkenyl" refers to an alkenyl group that also includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., interposed between adjacent carbon atoms) and/or at one or more terminal positions. In certain embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroc2-10Alkenyl "). In some embodiments, heteroalkenyl has 2 to 9 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain2-9Alkenyl "). In some embodiments, heteroalkenyl has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain2-8Alkenyl "). In some embodiments, heteroalkenyl has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain2-7Alkenyl "). In some embodiments, heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms ("heteroc") within the parent chain 2-6Alkenyl "). In some embodiments, heteroalkenyl has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain2-5Alkenyl "). In some embodiments, heteroalkenyl has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroc") within the parent chain2-4Alkenyl "). In some embodiments, heteroalkenyl has 2 to 3 carbon atoms in the parent chainAt least one double bond and 1 or 2 heteroatoms ('hetero C')2-3Alkenyl "). In some embodiments, heteroalkenyl has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroc") within the parent chain2-6Alkenyl "). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, heteroalkenyl is unsubstituted heteroc2-10An alkenyl group. In certain embodiments, heteroalkenyl is substituted heteroc2-10An alkenyl group.
The term "alkynyl" refers to a straight or branched chain hydrocarbyl group ("C") having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds)2-10Alkynyl "). In some embodiments, alkynyl has 2 to 9 carbon atoms ("C) 2-9Alkynyl "). In some embodiments, alkynyl groups have 2 to 8 carbon atoms ("C)2-8Alkynyl "). In some embodiments, alkynyl has 2 to 7 carbon atoms ("C)2-7Alkynyl "). In some embodiments, alkynyl has 2 to 6 carbon atoms ("C)2-6Alkynyl "). In some embodiments, alkynyl has 2 to 5 carbon atoms ("C)2-5Alkynyl "). In some embodiments, alkynyl groups have 2 to 4 carbon atoms ("C)2-4Alkynyl "). In some embodiments, alkynyl has 2 to 3 carbon atoms ("C)2-3Alkynyl "). In some embodiments, alkynyl has 2 carbon atoms ("C)2Alkynyl "). One or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C)2) 1-propynyl (C)3) 2-propynyl (C)3) 1-butynyl (C)4) 2-butynyl (C)4) And the like. C2-6Examples of the alkenyl group include the above-mentioned C2-4Alkynyl and pentynyl (C)5) Hexynyl (C)6) And the like. Additional examples of alkynyl groups include heptynyl (C)7) (C) octynyl group8) And so on. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (i.e., "unsubstituted)Substituted alkynyl ") or substituted with one or more substituents (" substituted alkynyl "). In certain embodiments, alkynyl is unsubstituted C 2-10Alkynyl. In certain embodiments, alkynyl is substituted C2-10Alkynyl.
The term "heteroalkynyl" refers to an alkynyl group that also contains at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., interposed between adjacent carbon atoms) and/or at one or more terminal positions. In certain embodiments, heteroalkynyl refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain2-10Alkynyl "). In some embodiments, heteroalkynyl has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain2-9Alkynyl "). In some embodiments, heteroalkynyl has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain2-8Alkynyl "). In some embodiments, heteroalkynyl has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain2-7Alkynyl "). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms ("heteroc") in the parent chain2-6Alkynyl "). In some embodiments, heteroalkynyl has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain 2-5Alkynyl "). In some embodiments, heteroalkynyl has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroc") within the parent chain2-4Alkynyl "). In some embodiments, heteroalkynyl has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroc") in the parent chain2-3Alkynyl "). In some embodiments, heteroalkynyl has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroc") in the parent chain2-6Alkynyl "). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In some implementationsIn the scheme, heteroalkynyl is unsubstituted heteroC2-10Alkynyl. In certain embodiments, heteroalkynyl is substituted heteroC2-10Alkynyl.
The term "carbocyclyl" or "carbocycle" refers to a ring having from 3 to 14 ring carbon atoms ("C") in a non-aromatic ring system3-14Carbocyclyl ") and a non-aromatic cyclic hydrocarbyl group of zero heteroatoms. In some embodiments, carbocyclyl has 3 to 10 ring carbon atoms ("C)3-10Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 8 ring carbon atoms ("C) 3-8Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 7 ring carbon atoms ("C)3-7Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 6 ring carbon atoms ("C)3-6Carbocyclyl "). In some embodiments, carbocyclyl has 4 to 6 ring carbon atoms ("C)4-6Carbocyclyl "). In some embodiments, carbocyclyl has 5 to 6 ring carbon atoms ("C)5-6Carbocyclyl "). In some embodiments, carbocyclyl has 5 to 10 ring carbon atoms ("C)5-10Carbocyclyl "). Exemplary C3-6Carbocyclyl includes, but is not limited to, cyclopropyl (C)3) Cyclopropenyl group (C)3) Cyclobutyl (C)4) Cyclobutenyl radical (C)4) Cyclopentyl (C)5) Cyclopentenyl group (C)5) Cyclohexyl (C)6) Cyclohexenyl (C)6) Cyclohexadienyl (C)6) And the like. Exemplary C3-8Carbocyclyl includes, but is not limited to, C as described above3-6Carbocyclyl and cycloheptyl (C)7) Cycloheptenyl (C)7) Cycloheptadienyl (C)7) Cycloheptatrienyl (C)7) Cyclooctyl (C)8) Cyclooctenyl (C)8) Bicyclo [2.2.1]Heptylalkyl radical (C)7) Bicyclo [2.2.2]Octyl radical (C)8) And the like. Exemplary C3-10Carbocyclyl includes, but is not limited to, C as described above3-8Carbocyclyl and cyclononyl (C)9) Cyclononenyl (C)9) Cyclodecyl (C)10) Cyclodecenyl (C)10) octahydro-1H-indenyl (C) 9) Decahydronaphthyl (C)10) Spiro [4.5 ]]Decyl (C)10) And the like. As the foregoing examples show, inIn certain embodiments, carbocyclyl is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems such as bicyclic systems ("bicyclic carbocyclyl") or tricyclic systems ("tricyclic carbocyclyl")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. "carbocyclyl" also includes ring systems in which a carbocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and in such cases the number of carbons continues to indicate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, carbocyclyl is unsubstituted C3-14A carbocyclic group. In certain embodiments, carbocyclyl is substituted C3-14A carbocyclic group.
In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl ("C") having 3 to 14 ring carbon atoms3-14Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 10 ring carbon atoms ("C) 3-10Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms ("C)3-8Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms ("C)3-6Cycloalkyl "). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms ("C)4-6Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms ("C)5-6Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms ("C)5-10Cycloalkyl "). C5-6Examples of cycloalkyl include cyclopentyl (C)5) And cyclohexyl (C)5)。C3-6Examples of cycloalkyl groups include the foregoing C5-6Cycloalkyl and cyclopropyl (C)3) And cyclobutyl (C)4)。C3-8Examples of the cycloalkyl group include the aforementioned C3-6Cycloalkyl and cycloheptyl (C)7) And cyclooctyl (C)8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (unsubstituted)Cycloalkyl ") or substituted with one or more substituents (" substituted cycloalkyl "). In certain embodiments, cycloalkyl is unsubstituted C3-14A cycloalkyl group. In certain embodiments, cycloalkyl is substituted C3-14A cycloalkyl group.
The term "heterocyclyl" or "heterocycle" refers to a 3 to 14-membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("C) 3-14A heterocyclic ring). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of a heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, a heterocyclyl is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-14 membered heterocyclyl.
In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, aziridinyl (azirdinyl), oxiranyl (oxiranyl), and thieranyl (thiiranyl). Exemplary 4-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azetidinyl (azetidinyl), oxetanyl (oxolanyl), and thietanyl (thietanyl). Exemplary 5-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxolanyl (dioxolanyl), oxathiolanyl (oxathiolanyl), and dithiopentanoyl (dithiolyl). Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl,
Figure BDA0001614314770000941
Diazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thioalkyl (thianyl). Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dithianyl
Figure BDA0001614314770000942
An alkyl group. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl (azepanyl), oxepanyl (oxepanyl), and thiepanyl (thiepanyl). Examples containing 1 heteroatomExemplary 8-membered heterocyclic groups include, but are not limited to, azacyclooctyl (azocanyl), oxocyclooctyl (oxocanyl), and thiacyclooctyl (thiocanyl). Exemplary bicyclic heterocyclic groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo [3, 2-b ] heterocyclyl ]Pyrrole, indolinyl, phthalimidyl, naphthaliminyl, chromanyl, chromenyl, 1H-benzo [ e ]][1，4]Diazepines
Figure BDA0001614314770000951
1, 4, 5, 7-tetrahydropyrano [3, 4-b ]]Pyrrolyl, 5, 6-dihydro-4H-furo [3, 2-b]Pyrrolyl, 6, 7-dihydro-5H-furo [3, 2-b]Pyranyl, 5, 7-dihydro-4H-thieno [2, 3-c]Pyranyl, 2, 3-dihydro-1H-pyrrolo [2, 3-b ]]Pyridyl, 2, 3-dihydrofuro [2, 3-b ]]Pyridyl, 4, 5, 6, 7-tetrahydro-1H-pyrrolo [2, 3-b ]]Pyridyl, 4, 5, 6, 7-tetrahydrofuro [3, 2-c ]]Pyridyl, 4, 5, 6, 7-tetrahydrothieno [3, 2-b ]]Pyridyl, 1, 2, 3, 4-tetrahydro-1, 6-naphthyridinyl, and the like.
The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in an array of rings) group having 6 to 14 ring carbon atoms and 0 heteroatom ("C") provided in the aromatic ring system6-14Aryl "). In some embodiments, an aryl group has 6 ring carbon atoms ("C)6Aryl "; such as phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C) 10Aryl "; for example naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C)14Aryl "; such as an anthracene group). "aryl" also includes those in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groupsWherein the linking group or point is on the aryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, aryl is unsubstituted C6-14And (4) an aryl group. In certain embodiments, aryl is substituted C6-14And (4) an aryl group.
"aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, wherein the point of attachment is on the alkyl moiety.
The term "heteroaryl" refers to a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in the ring array) group having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the point of attachment is on the aryl or heteroaryl ring, and in this case the number of ring members indicates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. The point of attachment of a polycyclic heteroaryl group wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) can be on either ring, i.e., a ring having a heteroatom (e.g., 2-indolyl) or a ring that does not contain a heteroatom (e.g., 5-indolyl).
In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of heteroaryl is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, heteroaryl is unsubstituted 5-14 membered heteroaryl. In certain embodiments, heteroaryl is substituted 5-14 membered heteroaryl.
Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, and,
Figure BDA0001614314770000961
Azolyl radical, iso
Figure BDA0001614314770000962
Oxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, and triazolyl,
Figure BDA0001614314770000963
Oxadiazolyl and thiadiazolyl groups. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Containing 2 hetero atomsExemplary 6-membered heteroaryl groups of (a) include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoimidazolyl
Figure BDA0001614314770000964
Azolyl, benzisoyl
Figure BDA0001614314770000965
Azolyl, benzo
Figure BDA0001614314770000966
Oxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl groups. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl (phthalazinyl), and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxathiin
Figure BDA0001614314770000967
An oxazinyl group and a phenazinyl group.
"heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
The addition of the suffix "-ene" to the group indicates that the group is a divalent moiety, e.g., alkylene (alkenylene) is a divalent moiety of alkyl, alkenylene (alkenylene) is a divalent moiety of alkenyl, alkynylene (alkynylene) is a divalent moiety of alkynyl, heteroalkylene (heteroalklyene) is a divalent moiety of heteroalkyl, heteroalkenylene (heteroalkenylene) is a divalent moiety of heteroalkenylene, heteroalkynylene (heteroalkynylene) is a divalent moiety of heteroalkynylene, carbocyclylene (carbocyclylene) is a divalent moiety of carbocyclyl, arylene (arylene) is a divalent moiety of aryl, and heteroarylene (heteroarylene) is a divalent moiety of heteroaryl.
Unless expressly provided otherwise, groups are optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted. "optionally substituted/optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). In general, the term "substituted" refers to the replacement of at least one hydrogen present on a group with an allowed substituent, e.g., substituent substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position is the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that result in the formation of stable compounds. The present invention contemplates any and all such combinations to obtain stable compounds. For purposes of the present invention, a heteroatom (e.g., nitrogen) can have a hydrogen substituent and/or any suitable substituent that satisfies the valence of the heteroatom and results in the formation of a stable moiety, as described herein. The present invention is not intended to be limited in any way by the exemplary substituents described herein.
Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)(Raa)2、-P(＝O)(ORcc)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)(N(Rbb)2)2、-OP(＝O)(N(Rbb)2)2、-NRbbP(＝O)(Raa)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(N(Rbb)2)2、-P(Rcc)2、-P(ORcc)2、-P(Rcc)3 +X-、-P(ORcc)3 +X-、-P(Rcc)4、-P(ORcc)4、-OP(Rcc)2、-OP(Rcc)3 +X-、-OP(ORcc)2、-OP(ORcc)3 +X-、-OP(Rcc)4、-OP(ORcc)4、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstitution of radicals; wherein X-is a counterion;
or two pairs of hydrogen (geminal hydrogen) on a carbon atom are substituted by a group ═ O, ═ S, ═ NN (R)bb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbbOr as NORccAnd (4) replacing.
RaaEach instance of (A) is independently selected from C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RaaThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein the alkyl, alkenyl, alkynylHeteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups;
Rbbeach instance of (A) is independently selected from hydrogen, -OH, -ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc) O-shaped forkaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)(Raa)2、-P(＝O)(ORcc)2、-P(＝O)(N(Rcc)2)2、C1-10Alkyl radical, C1-10Perhaloalkyl, C 2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RbbThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups; wherein X-Is a counter ion;
Rcceach instance of (A) is independently selected from hydrogen, C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independentlyGround is covered by 0, 1, 2, 3, 4 or 5RddSubstituted by groups;
Rddeach instance of (A) is independently selected from halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)(ORee)2、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, heteroaryl, or combinations thereof, Aryl and heteroaryl are each independently substituted by 0, 1, 2, 3, 4 or 5RggSubstituted by radicals, or two pairs of RddSubstituents may be linked to form ═ O or ═ S; wherein X-Is a counter ion;
Reeeach instance of (A) is independently selected from C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, C6-10Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RggSubstituted by groups;
Rffeach instance of (A) is independently selected from hydrogen, C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, 3-to 10-membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, or two RffThe groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RggSubstituted by groups; and is
RggEach instance of (A) is independently halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6Alkyl, -ON (C) 1-6Alkyl radical)2、-N(C1-6Alkyl radical)2、-N(C1-6Alkyl radical)3 +X-、-NH(C1-6Alkyl radical)2 +X-、-NH2(C1-6Alkyl radical)+X-、-NH3 +X-、-N(OC1-6Alkyl) (C1-6Alkyl), -N (OH) (C)1-6Alkyl), -NH (OH), -SH, -SC1-6Alkyl, -SS (C)1-6Alkyl) s,-C(＝O)(C1-6Alkyl), -CO2H、-CO2(C1-6Alkyl), -OC (═ O) (C)1-6Alkyl), -OCO2(C1-6Alkyl), -C (═ O) NH2、-C(＝O)N(C1-6Alkyl radical)2、-OC(＝O)NH(C1-6Alkyl), -NHC (═ O) (C)1-6Alkyl), -N (C)1-6Alkyl) C (═ O) (C)1-6Alkyl), -NHCO2(C1-6Alkyl), -NHC (═ O) N (C)1-6Alkyl radical)2、-NHC(＝O)NH(C1-6Alkyl), -NHC (═ O) NH2、-C(＝NH)O(C1-6Alkyl), -OC (═ NH) (C)1-6Alkyl), -OC (═ NH) OC1-6Alkyl, -C (═ NH) N (C)1-6Alkyl radical)2、-C(＝NH)NH(C1-6Alkyl), -C (═ NH) NH2、-OC(＝NH)N(C1-6Alkyl radical)2、-OC(NH)NH(C1-6Alkyl), -OC (NH) NH2、-NHC(NH)N(C1-6Alkyl radical)2、-NHC(＝NH)NH2、-NHSO2(C1-6Alkyl), -SO2N(C1-6Alkyl radical)2、-SO2NH(C1-6Alkyl), -SO2NH2、-SO2C1-6Alkyl, -SO2OC1-6Alkyl, -OSO2C1-6Alkyl, -SOC1-6Alkyl, -Si (C)1-6Alkyl radical)3、-OSi(C1-6Alkyl radical)3-C(＝S)N(C1-6Alkyl radical)2、C(＝S)NH(C1-6Alkyl), C (═ S) NH2、-C(＝O)S(C1-6Alkyl), -C (═ S) SC1-6Alkyl, -SC (═ S) SC1-6Alkyl, -P (═ O) (OC)1-6Alkyl radical)2、-P(＝O)(C1-6Alkyl radical)2、-OP(＝O)(C1-6Alkyl radical)2、-OP(＝O)(OC1-6Alkyl radical)2、C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, C6-10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two paired RggThe substituents may beLinked to form ═ O or ═ S; wherein X-Is a counter ion.
The term "halo" or "halogen" refers to fluoro (fluoro, -F), chloro (chloro, -Cl), bromo (bromo, -Br), or iodo (iodo, -I).
The term "hydroxyl" or "hydroxide" refers to the group-OH. The related terms "substituted hydroxy" or "substituted hydroxy" refer to a hydroxy group in which the oxygen atom directly attached to the parent molecule is replaced with a group other than hydrogen, and include groups selected from: -ORaa、-ON(Rbb)2、-OC(＝O)SRaa、-OC(＝O)Raa、-OCO2Raa、-OC(＝O)N(Rbb)2、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-OC(＝NRbb)N(Rbb)2、-OS(＝O)Raa、-OSO2Raa、-OSi(Raa)3、-OP(Rcc)2、-OP(Rcc)3 +X-、-OP(ORcc)2、-OP(ORcc)3 +X-、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2and-OP (═ O) (N (R)bb))2Wherein X is-、Raa、RbbAnd RccAs defined herein.
The term "amino" refers to the group-NH2. The term "substituted amino" in the context of this application refers to mono-, di-or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono-substituted amino or di-substituted amino group.
The term "monosubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from: -NH (R)bb)、-NHC(＝O)Raa、-NHCO2Raa、-NHC(＝O)N(Rbb)2、-NHC(＝NRbb)N(Rbb)2、-NHSO2Raa、-NHP(＝O)(ORcc)2and-NHP (═ O) (N (R)bb)2)2Wherein R isaa、RbbAnd RccAs defined herein, and wherein the group-NH (R)bb) R of (A) to (B)bbIs not hydrogen.
The term "disubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from: -N (R)bb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-NRbbSO2Raa、-NRbbP(＝O)(ORcc)2and-NRbbP(＝O)(N(Rbb)2)2Wherein R isaa、RbbAnd RccAs defined herein, provided that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups and includes groups selected from the group consisting of-N (R)bb)3and-N (R)bb)3 +X-Wherein R isbbAnd X-As defined herein.
The term "acyl" refers to a compound having the formula-C (═ O) RX1、-C(＝O)ORX1、-C(＝O)-O-C(＝O)RX1、-C(＝O)SRX1、-C(＝O)N(RX1)2、-C(＝S)RX1、-C(＝S)N(RX1)2and-C (═ S) S (R)X1)、-C(＝NRX1)RX1、-C(＝NRX1)ORX1、-C(＝NRX1)SRX1and-C (═ NR)X1)N(RX1)2Wherein R isX1Is hydrogen; halogen; substituted or unsubstituted hydroxy; a substituted or unsubstituted thiol group (thiol); a substituted or unsubstituted amino group; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substitutedOr an unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkylsulfoxy, heteroalkylsulfoxy, arylsulfenoxy, heteroarylsulfoxy, mono-or di-aliphatic amino, mono-or di-heteroaliphatic amino, mono-or di-alkylamino, mono-or di-heteroalkylamino, mono-or di-arylamino or mono-or di-heteroarylamino; or two R X1The groups together form a 5 to 6 membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO)2H) Ketones, acid halides, esters, amides, imines, carbonates, carbamates and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thio (thiooxo), cyano, isocyano, amino, azido, nitro, hydroxy, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkylsulfoxy, heteroalkylsulfoxy, arylsulfenoxy, heteroarylsulfoxy, acyloxy, and the like, each of which may or may not be further substituted).
The term "carbonyl" refers to a group in which the carbon directly attached to the parent molecule is sp2Groups hybridized and substituted with oxygen, nitrogen or sulfur atoms, such as groups selected from: ketone (-C (═ O) R aa) Carboxylic acid (-CO)2H) Aldehyde (-CHO), ester (-CO)2Raa、-C(＝O)SRaa、-C(＝S)SRaa) Amide (-C (═ O) N (R)bb)2、-C(＝O)NRbbSO2Raa、-C(＝S)N(Rbb)2) And imines (-C (═ NR)bb)Raa、-C(＝NRbb)ORaa)、-C(＝NRbb)N(Rbb)2) Wherein R isaaAnd RbbAs defined herein.
The term "oxo" refers to the group ═ O, and the term "thio" refers to the group ═ S.
The nitrogen atoms may be substituted or unsubstituted as valency permits and include primary, secondary, tertiary and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRCc)ORaa、-C(＝NRCc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)(ORcc)2、-P(＝O)(Raa)2、-P(＝O)(N(Rcc)2)2、C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two R attached to the N atomccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddIs substituted and wherein Raa、Rbb、RccAnd RddAs defined above.
In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as an oxygen protecting group)As a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to-Raa、-N(Rbb)2、-C(＝O)SRaa、-C(＝O)Raa、-CO2Raa、-C(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-S(＝O)Raa、-SO2Raa、-Si(Raa)3、-P(Rcc)2、-P(Rcc)3 +X-、-P(ORcc)2、-P(ORcc)3 +X-、-P(＝O)(Raa)2、-P(＝O)(ORcc)2and-P (═ O) (N (R)bb)2)2Wherein X is-、Raa、RbbAnd RccAs defined herein. Oxygen Protecting Groups are well known in the art and include Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, 3 rd edition, John Wiley &Sons, 1999, which is incorporated herein by reference.
In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to-Raa、-N(Rbb)2、-C(＝O)SRaa、-C(＝O)Raa、-CO2Raa、-C(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-S(＝O)Raa、-SO2Raa、-Si(Raa)3、-P(Rcc)2、-P(Rcc)3 +X-、-P(ORcc)2、-P(ORcc)3 +X-、-P(＝O)(Raa)2、-P(＝O)(ORcc)2and-P (═ O) (N (R)bb)2)2Wherein X is-、Raa、RbbAnd RccAs defined herein. Oxygen Protecting Groups are well known in the art and include Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, 3 rd edition, John Wiley&Sons, 1999, which is incorporated herein by reference.
A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electrical neutrality. The anionic counterions can be monovalent (i.e., contain one formal negative charge). The anionic counterion may also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F)-、Cl-、Br-、I-)、NO3 -、ClO4 -、OH-、H2PO4 -、HCO3 -、HSO4 -Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF 4 -、PF4 -、PF6 -、AsF6 -、SbF6 -、B[3，5-(CF3)2C6H3]4]-、B(C6F5)4 -、BPh4 -、Al(OC(CF3)3)4 -And carborane anions (e.g., CB)11H12 -Or (HCB)11Me5Br6)-). Exemplary counterions that can be multivalent include CO3 2-、HPO4 2-、PO4 3-、B4O7 2-、SO4 2-、S2O3 2-Carboxylate anions (e.g. tartrate, citrate, fumarate, maleate)Malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.
As used herein, the use of the phrase "at least one example" refers to 1, 2, 3, 4, or more examples, but also encompasses ranges such as 1 to 4, 1 to 3, 1 to 2, 2 to 4, 2 to 3, or 3 to 4 examples, inclusive.
"non-hydrogen group" refers to any group defined for a particular variable other than hydrogen.
The term "polysaccharide" refers to a polymer composed of long chain or monosaccharide units of a carbohydrate, or a derivative thereof (e.g., a monosaccharide modified to contain cross-linkable functional groups). Exemplary polysaccharides include, but are not limited to, polysaccharides, dextran, starch, glycogen, arabinoxylan, cellulose, hemicellulose, chitin, pectin, dextran, pullulan, laminarin (chrysospamin), curdlan (curdlan), laminarin (laminarin), lentinan, lichenin (lichenin), pleuran, zymosan, glycosaminoglycans (glycosaminoglycans), dextran, hyaluronic acid, chitosan, and chondroitin. Monosaccharide monomers of polysaccharides are usually linked by glycosidic linkages (glysolidic linkages). Polysaccharides may be hydrolyzed to form oligosaccharides, disaccharides, and/or monosaccharides. The term "carbohydrate" or "sugar" refers to an aldehyde or ketone derivative of a polyol. Monosaccharides are the simplest carbohydrates because they cannot be hydrolyzed to smaller carbohydrates. Most monosaccharides can be represented by the general formula C yH2yOy(e.g., C)6H12O6(hexose, e.g., glucose)) wherein y is an integer equal to or greater than 3. Certain polyols not represented by the above general formula are also considered monosaccharides. For example, the deoxyribose is of formula C5H10O4And is a monosaccharide. Monosaccharides are usually composed of five or six carbon atoms and are called pentoses and hexoses, respectively. If the monosaccharide contains an aldehyde, it is called aldose; if it contains a ketone, it is referred to as ketose. The monosaccharide may also be comprised of a tri-aldose or ketose formOne, four or seven carbon atoms, referred to as triose, tetrose and heptose, respectively. Glyceraldehyde and dihydroxyacetone are known as aldotriose sugar and methylglucose, respectively. Examples of aldotetroses include erythrose and threose; the ketobutyrate includes erythrulose. Aldopentoses include ribose, arabinose, xylose, and lyxose; ketopentoses include ribulose, arabinose, xylulose (xylulose) and xylulose (lyxulose). Examples of aldohexoses include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; hexulose includes fructose, psicose, sorbose, and tagatose. The heptulose includes sedoheptulose. Except for the first and last carbons, each carbon atom of the monosaccharide bearing a hydroxyl (-OH) group is asymmetric, making the carbon atom a stereocenter with two possible configurations (R or S). Because of this asymmetry, many isomers may exist for any given monosaccharide formula. For example, aldohexose D-glucose has formula C 6H12O6All but two of its six carbon atoms are stereoisomeric, resulting in a D-glucose of 16 species (i.e., 2)4One) of the possible stereoisomers. The assignment of D or L is made according to the orientation of the asymmetric carbon atom furthest from the carbonyl group: in the standard Fischer projection, if the hydroxyl group is located on the right, the molecule is the D saccharide, otherwise it is the L saccharide. The aldehyde or ketone group of a linear monosaccharide reacts reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, thereby forming a heterocyclic ring having an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and there is an equilibrium with the linear form. During the transition from the linear to the cyclic form, the carbon atom containing the carbonyl oxygen (called the anomeric carbon) becomes a stereogenic center with two possible configurations: the oxygen atom may be located above or below the plane of the ring. The resulting possible stereoisomer pairs are called anomers. In the alpha anomer, the-OH substituent on the anomeric carbon is located in the ring and the-CH2The OH side branches off the opposite side (trans). wherein-CH2Another form in which the OH substituent and the anomeric hydroxyl group are located on the same side of the ring plane (cis) is known as the β anomer. Operation of the art The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.
Other definitions
Animals: as used herein, the term animal refers to humans as well as non-human animals, including, for example, mammals, birds, reptiles, amphibians, and fish. Preferably, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a primate, or a pig). The non-human animal can be a transgenic animal.
About or about: as used herein, the term "about" or "approximately" with respect to a number is generally considered to include numbers that fall within 5%, 10%, 15%, or 20% of either direction (greater than or less than) the number unless otherwise indicated or otherwise evident from the context (unless such numbers would be less than 0% or more than 100% of the possible value).
Biocompatibility: as used herein, the term "biocompatible" refers to a substance that is non-toxic to cells. In some embodiments, a substance is considered "biocompatible" if the addition of the substance to a cell in vivo does not induce inflammation and/or other side effects in vivo. In some embodiments, a substance is considered "biocompatible" if addition of the substance to a cell in vitro or in vivo results in less than or equal to about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, or less than about 5% cell death.
And (3) biodegradation: as used herein, the term "biodegradable" refers to a substance that degrades under physiological conditions. In some embodiments, the biodegradable substance is a substance that is broken down by cellular machinery. In some embodiments, the biodegradable substance is a substance that breaks down by a chemical process.
Optical transparency: as used herein, the term "optically transparent" refers to a substance through which light passes with little or no absorption or reflection of light. In some embodiments, optically transparent refers to a substance through which light passes without being absorbed or reflected. In some embodiments, optically transparent refers to a substance through which light passes and little light is absorbed or reflected. In some embodiments, the optically transparent substance is substantially clear. In some embodiments, the optically transparent substance is clear.
Effective amount: generally, an "effective amount" of an active agent refers to an amount sufficient to elicit a desired biological response. As will be appreciated by one of ordinary skill in the art, an effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the patient. An effective amount of a compound for treating an infection is the amount required to kill or prevent the growth of the organism causing the infection.
In vitro: as used herein, the term "in vitro" refers to an event that occurs in an artificial environment, such as in a test tube or reaction vessel, in a cell culture, and the like, rather than within an organism (e.g., an animal, plant, and/or microorganism).
In vivo: as used herein, the term "in vivo" refers to an event that occurs within an organism (e.g., an animal, plant, and/or microorganism).
Has the following symptoms: an individual suffering from a "disease, disorder, and/or condition" has been diagnosed with or exhibiting one or more symptoms of the disease, disorder, and/or condition.
Treatment: as used herein, the term "treating" refers to partially or completely alleviating, ameliorating, alleviating, delaying onset, inhibiting progression, reducing severity, and/or reducing incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. For example, "treating" a microbial infection may refer to inhibiting the survival, growth, and/or spread of a microorganism. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition to reduce the risk of developing a pathology associated with the disease, disorder, and/or condition. In some embodiments, the treatment comprises delivering the vaccine nanocarriers of the invention to the subject.
Therapeutic agents: also referred to as "drugs," are used herein to refer to agents administered to a subject to treat a disease, disorder, or other clinically recognized condition that is harmful to the subject, or for prophylactic purposes, and have a clinically significant effect on the body to treat or prevent the disease, disorder, or condition. Therapeutic agents include, but are not limited to, the agents listed in: united States Pharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 th edition, McGraw Hill, 2001; katzung, B. (eds.) Basic and Clinical Pharmacology, McGraw-Hill/Appleton & Lange; 8 th edition (9 months and 21 days in 2000); physician's Desk Reference (Thomson Publishing), and/or The Merck Manual of Diagnosis and Therapy, 17 th edition (1999), or 18 th edition after its publication (2006), Mark H.Beers and Robert Berkow (ed.), Merck Publishing Group, or in The case of animals, The Merck Veterinary Manual, 9 th edition, Kahn, C.A. (eds.), Merck Publishing Group, 2005.
Diagnostic agent(s): as used herein, the term "diagnostic agent" refers to an agent that is administered to a subject to aid in the diagnosis of a disease, disorder, or condition. In some embodiments, the diagnostic agent is used to define and/or characterize the location of a pathological process. Diagnostic agents include X-ray contrast agents, radioisotopes, and dyes.
Surfactant (b): as used herein, the term "surfactant" refers to any agent that preferentially absorbs at the interface between two immiscible phases (e.g., the interface between water and an organic solvent, the water/air interface, or the organic solvent/air interface). Surfactants typically have a hydrophilic portion and a hydrophobic portion. Surfactants may also facilitate the flux of therapeutic or diagnostic agents across biological membranes (e.g., the tympanic membrane).
Terpene: as used herein, the term "terpene" refers to any agent derived, for example, from biosynthesis or believed to be derived from an isoprene unit (five carbon unit). For example, the isoprene units of a terpene may be linked together to form a straight chain, or they may be arranged in a ring. Typically, the terpenes disclosed herein facilitate the flux of a therapeutic or diagnostic agent across a biological membrane (e.g., the tympanic membrane). Terpenes can be of natural origin or synthetically prepared.
The terms "composition" and "formulation" are used interchangeably.
Examples
In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting the scope thereof.
Materials and methods
The method and the design are as follows: the experiment compared the effect of the introduction of polymer matrix and CPE on TM permeability and OM cure rate. For ex vivo experiments, a sample size of 4 was selected for each formulation, which can provide 80% efficacy (power) to detect 50% flux differences based on efficacy analysis using a non-parametric Friedman test (version 7.0, nQuery Advisor, Statistical Solutions, saurus, MA). Sample sizes of 8-10 were used for in vivo experiments, which were supported by previous publications (Pelton et al, Antimicrob. Agents Chemother.44, 654-657 (2000)). A Fisher exact test was used to assess the comparison between positive and negative efficacy results. Statistical analysis was performed using SAS software (version 9.2, SAS Institute, Cary, NC). To control type I errors, a two-tailed p < 0.05 with appropriate Bonferroni-Sidak adjustments for multiple comparisons was considered statistically significant. During the ex vivo experiments, data collection was stopped after 48 hours due to microbial growth on the harvested TM; during the in vivo experiments, data collection was stopped after 7 days, as OM would be cleared or cause the animals to have severe disease requiring euthanasia. In vivo experiments were blind. All experiments were randomized.
Materials: using 2-chloro-2-oxo-1, 3, 2-dioxaphospholane (COP), 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU), n-butanol, diethyl ether, acetic acid, anhydrous dichloromethane, anhydrous tetrahydrofuran, received from Sigma-Aldrich Company (St. Louis, Mo.).
Figure BDA0001614314770001071
P407 microprilled (poloxamer 407) was received from BASF (Florham Park, NJ).
Animal maintenance: healthy adult male chinchillas weighing 500 to 650g were purchased from Ryerson chinchialla Ranch (Plymouth, OH) and were cared for according to institutional and national approved protocols. The experiments were performed according to Boston Children's Hospital, Boston University Medical Center, and Massachusetts Eye and Ear Medical Animal Use Guidelines, approved by the Animal Care and Use Committee of the various institutions.
Hydrogel formation: the P407-PBP hydrogel formulation was prepared by adding powdered polymer to an aqueous solution. Gels of different weight percentages of P407-PBP (10% to 18%) can be prepared by simple dissolution in a cold room to allow better solubility.
Gel time: the hydrogel formulation in scintillation vials (scintillation visual) was immersed in a water bath maintained at 37 ℃ under constant stirring (200 rpm). The time the stir bar stopped rotating after immersion was recorded as the gel time.
And (3) gelling temperature: measurement of shear rheology Using Linear Oscillating (100 rads)-11% strain, 1 ℃ min-1) The gelation temperature was quantified. The gelation temperature is taken as the temperature at which the storage modulus (G ') becomes greater than the loss modulus (G'). Changes in G' and G "from 0 ℃ to temperatures above body temperature were recorded to reflect changes in mechanical properties.
In vitro release studies: the release of ciprofloxacin in each formulation was measured using a diffusion system. Use of
Figure BDA0001614314770001083
Membrane insert (0.4 μm pore size, 1.1 cm)2Area; costar, Cambridge, MA) and 24-well plates served as donor and recipient chambers, respectively. 200 μ L of each formulation was pipetted directly onto the pre-heated filter insert to obtain a solid hydrogel. The filter insert (donor chamber) with the formed gel is suspended in a fillingPre-warmed Phosphate Buffered Saline (PBS) wells (recipient chamber) and plates were then incubated in a 37 ℃ oven. At each time point (0.5, 1, 2, 6, 12, 24, 48h), a 1mL aliquot of PBS receiving medium was taken and inserts were sequentially transferred into new wells with fresh PBS. Aliquots were suspended in 70: 30 acetonitrile/PBS to ensure total drug dissolution. An aliquot of the sample was chromatographed by HPLC to determine ciprofloxacin concentration (λ 275 nm). More detailed information on ciprofloxacin measurements and HPLC conditions can be found in reference (8). Experiments were performed in quadruplicate.
In vitro permeation experiment: transTM permeation rates of ciprofloxacin were determined using auditory bulbs (audiory bullae) harvested from healthy chestnut rats. All formulations were applied to a bubble held at 37C and deposited on the TM. The volume applied was 200 μ L, which converted to 2mg ciprofloxacin. Ciprofloxacin permeation across the TM into the receiving chamber was quantified using HPLC. Detailed information on the configuration of TM harvesting, TM resistance measurement and in vitro permeation experiments can be found in reference (8).
Cytotoxicity assay: by using tetrazoles
Figure BDA0001614314770001084
The compound [3- (4, 5-dimethyl-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole
Figure BDA0001614314770001085
Internal salt; MTS]Mitochondrial metabolic activity assay CellTiter with Electron coupling agent (phenazine Ether sulfate; PES)
Figure BDA0001614314770001081
Aqueous One Solution Cell Proliferation Assay (Promega Corp.) to assess Cell viability. Human dermal fibroblasts (hFB), PC12, and normal adult primary epidermal keratinocytes (ATCC) were used with CellTiter on days 1 and 3 of culture
Figure BDA0001614314770001082
The Aqueous One Solution was incubated at 37 ℃ for 120 minutes. Ready to use 96 well plate readingsThe instrument records the absorbance of the medium at 490 nm. Formazan measured by absorbance at 490nm
Figure BDA0001614314770001086
The amount of product (converted from tetrazole) is directly proportional to the metabolic activity of the cells in culture. Planar cultures on 24-well plates were used as controls. For each group, n is 4. Use of LIVE-
Figure BDA0001614314770001091
Cell Viability was confirmed by the viatility/cytoxicity Kit (Molecular Probes, Invitrogen). Cells were incubated with 1. mu.M calcein-AM and 2. mu.M ethidium bromide homodimer-1 (EthD-1) at 37 ℃ for 30 min to label live and dead cells, respectively. Cell viability was calculated as live/(live + dead) × 100.
Histopathology: the formulation was administered to the ear canal of live healthy/OM chinchillas. Seven days later, they were euthanized as described elsewhere (8). After sacrifice, the TM was excised from boston children hospital pathology using standard techniques and immediately fixed in 10% neutral buffered formalin overnight, then decalcified, paraffin embedded, sectioned (5 μm thick) and stained with hematoxylin and eosin (pay per service). All stained specimens were evaluated under light microscopy (Olympus FSX-100).
Auditory Brainstem Response (ABR) measurement: ABR experiments were performed using a custom designed stimulus generation and measurement system built around National Instruments (Austin, TX) software (Lab View) and hardware. Detailed information about ABR can be found in reference (8).
NTHi OM model and pharmacokinetics: all procedures and procedures were performed at the boston university medical center with sedation and analgesia of an intramuscularly administered ketamine and xylazine mixture according to an approved IACUC protocol. Baseline plasma samples were obtained through the cranial sinuses 24 hours prior to bacterial inoculation. NTHi isolates grown to mid-log phase were diluted with HBSS and approximately 25-75cfu in 100 μ L were introduced directly into each middle ear vesicle under sterile conditions. Tympanometry and otomicroscopy were performed daily to determine in the auditory vacuole And the presence of infectious conditions, including tympanic membrane protrusion. Erythema (Erythema) and photographs were taken. Once an abnormality was identified, the middle ear cavity was approached after 48 to 72 hours as previously described (see Sabharwal et al, infection. immun.77, 1121-. Direct cultures of the middle ear were obtained with calcium alginate swabs and immediately streaked onto blood agar plates. Middle ear fluid was obtained using a 22 gauge vascular catheter connected to an empty tuberculin syringe and 10-20 μ L of middle ear fluid was diluted 1: 10 in HBSS to prepare three serial 10-fold dilutions. 100 microliters of each dilution was plated on blood agar. The lower limit of detection of living organisms in middle ear fluid using this dilution series was 100cfu mL-1. Direct and indirect ear examinations were performed every 1 to 2 days until the middle ear cultures were sterile. Serial plasma samples were obtained during the experiment to determine systemic drug levels.
Statistical analysis: data for normal distributions are described as mean and standard deviation and compared with unpaired student's t-test. Alternatively, the data are expressed as median ± quartile. All data analyses were performed using Origin 8 software.
Method and results
Isolation of intact chinchilla TM
The tympanic membrane size, middle ear structure and auditory range of chinchillas are very close to humans. Reproducible ex vivo methods for studying flux across the Tympanic Membrane (TM) have been established. The TM was removed without loss, still adhering to the bony tympanic ring. In a setting where the TM is placed horizontally in a 12-well plate (donor solution on top and receiver solution on the bottom), its integrity is assessed by measuring its resistance (by RA ≧ 18kOhm cm) 2Indication). The same setup was used to measure drug flux, which replaced the conventional diffusion cell, which would deform or rupture the TM. Skin samples with poorer reproducibility than TM were only used as screening tools to minimize animal use.
Transtympanic delivery of antibiotics
For trans-tympanic delivery of the antibiotic ciprofloxacin, synthetic fluoroquinolone antibiotics were selected because of their known activity against non-typable Haemophilus influenzae (NTHi) and Streptococcus Pneumoniae (SP), low molecular weight and moderate lipophilicity.
CPE enhances drug flux across intact TM
Sodium dodecyl sulfate (SDS; anionic surfactants) and limonene (monocyclic terpenes) were chosen as Chemical Permeation Enhancers (CPEs) based on their use in transdermal drug delivery and their advantageous enhancement/stimulation ratios. [28] Bupivacaine, an aminoamide local anesthetic, is incorporated into some formulations due to the potential clinical benefit of OM-related ear pain, and due to the aminoester anesthetic (e.g., tetracaine) as CPE. [15] In the absence of CPE, by 12 hours, the penetration of ciprofloxacin through chinchillas TM was undetectable at 37 ℃. At 24 hours, 109 μ g (in 2mg total ciprofloxacin) or 5.5% of the initial drug load had permeated the TM; at 48 hours 364. mu.g (18%) had penetrated. The addition of limonene can promote drug permeation; ciprofloxacin was detected in the receiving buffer as early as 1-2 hours. A 2-3 fold concentration-dependent increase in ciprofloxacin transfer at 48 hours was also achieved. The penetration of ciprofloxacin was further enhanced by using all three CPEs together (1% SDS, 0.5% bupivacaine and 2% limonene; referred to as 3 CPE).
Hydrogel at TM
During the experiment, the hydrogel component poloxamer 407(P407) was used to hold the drug-CPE combination in place at the TM. The 18% P407 loaded formulation formed a soft, clear gel when deposited on chinchilla TM at 37 ℃. The hydrogel matrix slowed trans-tympanic transfer of ciprofloxacin (figure 3). Addition of 3CPE increased flux (but still did not reach the level of ciprofloxacin + CPE without gel) such that 3 μ g ciprofloxacin passed through the TM after 6 hours and 14 μ g after 12 hours (fig. 3). This increase was seen at all time points, with 3CPE almost doubling the amount of ciprofloxacin that passed through the TM at 120 hours (812 μ g versus 441 μ g). The ciprofloxacin formulation in 18% P407 with 3CPE is referred to below as the standard formulation.
Biocompatibility
In vivo, TM mild edema, but no inflammation, was exposed to ciprofloxacin-loaded gel without 3CPE for 7 days (fig. 2). A slightly more pronounced edema was seen in tissues exposed to ciprofloxacin-loaded gel with 3CPE, but again the tissue response was benign. In contrast, TM extracted 7 days after untreated haemophilus influenzae infection was about 5 times thicker and showed a significant neutrophilic inflammatory response.
Measurement of Auditory Brainstem Response (ABR)
The drug-CPE-hydrogel should not affect the hearing threshold or be ototoxic. ABR threshold after application of the gel enhancer formulation was similar to the measurements before application (fig. 4).
Chinchilla model of OM
The infectious inoculum was placed in the middle ear through the superior bleb (super balloon) so that there was no opening of infection through the TM lesion and the drug flux through the TM would not be affected by the inoculation itself. In this way 100% of animals treated with Streptococcus Pneumoniae (SP) and non-typable haemophilus influenzae (NTHi) developed OM. In studies with a single NTHi strain, OM is eliminated in about 50% of animals treated with the standard formulation (20% relative to untreated animals). Ciprofloxacin was not detectable in the blood.
A relatively low cure rate may reflect insufficient in vivo drug flux and may be due to the following factors. 1) Insufficient drug load and/or CPE load. 2) Poor mechanical properties of the gel. At 27 ℃, the introduction of CPE changed the phase change of the P407 solution (fig. 5) so that the storage modulus did not become greater than the loss modulus, i.e., no gelation occurred. Although gelation still occurred at 37 ℃, these data indicate that gelation is not mechanically robust. This view is consistent with the finding in otoscopy that the gel based on P407 spreads in the ear canal; lack of bioadhesive is another possible contributing factor. Another problem is that gelation takes about 20 seconds. This may be sufficient in anesthetized animals, but not in active young children.
Synthesis of P407-PPE Polymer
The hydrophobic monomer 2-butoxy-2-oxo-1, 3, 2-dioxolane (BP) was prepared by condensation of 2-chloro-2-oxo-1, 3, 2-dioxolane (COP) with butanol, then purified by vacuum distillation and analyzed by proton and phosphorus NMR spectroscopy. Hydrophobic P407-PPE polymers (PBP-P407-PBP) were synthesized by ring-opening polymerization (ROP) of BP with P407 in the presence of an organic catalyst 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) at-20 ℃. After the reaction was complete (complete consumption of monomer was confirmed by NMR spectroscopy), excess acetic acid in Dichloromethane (DCM) was added to the reaction mixture to quench the reaction. The product was purified by precipitation in ether (3 times) and dried under vacuum to a white powder. Proton and phosphorous NMR spectroscopy, fourier transform infrared spectroscopy (FTIR), and gel permeation chromatography were used to characterize the polymer and confirm its purity. The FTIR spectra of the product PBP-P407-PBP and the starting material P407 are compared in FIG. 9. The molecular weight of the copolymer was 30.2kDa as measured by gel permeation chromatography.
Synthesis of P407-PPE Polymer
1, 8-diazabicyclo [5.4.0] at-20 ℃ in the presence of an organic catalyst]Pentablock copolymer P407-polybutylphosphate having n-butyl (FIG. 11A) or sec-butyl pendant groups (FIG. 11B) was synthesized by ring-opening polymerization (ROP) in the presence of undec-7-ene (DBU). After purification by precipitation, Fourier transform Infrared Spectroscopy (FTIR, FIGS. 11A-11B) is shown at 1650 and 1050cm -1Nearby peaks, Characteristic of O ═ P-O and P-O extensions in The polybutyl phosphate (PBP) moiety (Lin-Vien et al, The Handbook of isolated and Raman spectra frequency of Organic Molecules (Academic Press, New York) (1991)). Both are present in the spectrum of the ROP product, but not in reactant P407, indicating successful addition of the PPE block. The increase in molecular weight demonstrated by gel permeation chromatography (GPC, Table S1) indicated that P407 was chemically modified by n-butyl PBP or sec-butyl PBP blocks, not a physical mixture. Number average molecular weight (M) measured by Nuclear Magnetic Resonance (NMR)n) In agreement with that calculated from the chemical formula (table S1). M by GPCnAbout 30% higher than measured using NMR; this difference is well documented in the literature (Wong et al, ACS Macro Lett.1, 1266-. In this synthetic scheme, the small Degree of Polymerization (DP) is intended to avoid temperatures at or below room temperatureGelling and promoting the degradation of the hydrogel. The actual DP of the PPE block was determined to be 5 using NMR (FIG. 12A). Fig. 12A depicts Nuclear Magnetic Resonance (NMR) of the pentablock copolymer. DP was calculated using the peak area ratio of 0.90ppm (monomer side chain) and 1.14ppm (P407 backbone). The chemical shifts (δ, in ppm) of the peaks corresponding to the italic hydrogen in the following list of polymers are provided below. t/m/width indicates the shape of the peak (i.e., triplet, multiplet, broad). CDCl 3Is a solvent. For a P407-PBP with n-butyl,1H NMR(CDCl3，ppm)：δ0.90-0.96(t，3H，CH2CH2CH2CH3)，1.14(m，3H，CH2CH(CH3)O)，1.36-1.46(m，2H，CH2CH2CH2CH3)，1.62-1.72(m，2H，CH2CH2CH2CH3)，3.36-3.42(m，CH2CH(CH3)O)，3.48-3.58(m，2H，CH2CH(CH3)O)，3.65(m，4H，OCH2CH2O)，4.04-4.14(m，2H，PCH2CH2CH2CH3) 4.16-4.30 (Width, 4H, POCH)2CH2O). For P407-PBP with sec-butyl,1H NMR(CDCl3，ppm)：δ0.90-0.96(t，3H，CH3CHCH2CH3)，1.13(m，3H，CH2CH(CH3)O)，1.30-1.34(b，3H，CH3CHCH2CH3)，1.55-1.73(m，2H，CH3CHCH2CH3)，3-35-3.42(m，CH2CH(CH3)O)，3.48-3.58(m，2H，CH2CH(CH3)O)，3.65(m，4H，OCH2CH2O)，4.11-4.19(m，1H，CH3CHCH2CH3) 4.19-4.35 (Width, 4H, POCH)2CH2O). A smaller DP, e.g., DP 2.5, resulted in a high gelation temperature and poor shear strength (fig. 12B). P407-PBP with n-butyl and DP 5 was used in subsequent studies because it gelled at lower temperatures and had a higher shear modulus than those prepared with sec-butyl (fig. 12B).
Table S1 molecular weight and polydispersity index (polydispersity index) of P407 and of a pentablock copolymer P407-PBP having n-butyl or sec-butyl groups, measured by GPC and NMR.
Figure BDA0001614314770001131
Gel Properties of P407-PPE polymers
A commercial 18% aqueous solution of P407 (i.e., 18% [ P407 ]) that showed reverse thermal gelation]) Previously was a vehicle for the delivery of ciprofloxacin, an antibiotic with CPE, to the TM (8). For 18% [ P407]Storage (G ') and loss (G') moduli (at 100rads by linear oscillatory shear rheology -11% strain, 1 ℃ min-1Measured below) at room temperature was-1 kPa; it behaves as a viscous liquid. G 'and G' showed sharp increases at room temperature above 27 deg.C and plateaus at 6kPa and 4kPa, respectively (FIG. 13A), showing solid-like behavior. However, when 3CPE was added to the P407 solution at the desired concentration (previously used to enhance penetration through the TM (8)), the storage and loss moduli of the formulation were less than 2kPa (fig. 13B) at a temperature range of 20-40 ℃, i.e., the material did not form a gel in the presence of 3 CPE.
P407-PBP has faster gelation kinetics than unmodified P407. The sol-gel transition took place about 7 seconds after the Cip-3 CPE-18% [ P407-PBP ] was immersed in a water bath at 37 ℃ while the Cip-3 CPE-18% [ P407] remained in solution for 48 seconds. Cip-18% [ P407] and Cip-18% [ P407-PBP ] (in the absence of 3 CPE) showed the same gelation kinetics.
The inclusion of 3CPE did not prevent the gelation of P407-PBP. Linear oscillatory shear rheology measurement (100 rads)-11% strain, 1 ℃ min-1) Indicating that Cip-18% [ P407-PBP ]]Storage (G ') and loss (G') moduli at room temperature were 0.3 and 1.0kPa, respectively (FIG. 13C). Both G 'and G' were gradually increased in the temperature range of 27-38 deg.C and became 7.8 and 5.0kPa, respectively, at approaching body temperature. The sol-gel transition temperature was-33 ℃. To Cip-18% [ P407-PBP ]]Incorporation of 3CPE increased its storage modulus by more than 2.5-fold (fig. 13D). G' and G "increased from near zero at room temperature to 20 and 1.3kPa, respectively, at 37 ℃. The polymer solution exhibits a sol temperature of 20 DEG C-gel transition temperature. Micelles were observed by TEM at the low polymer concentration (1%) required for imaging mode.
To evaluate the effect of CPE alone on temperature-dependent mechanical properties, 1% SDS, 2% limonene, or 0.5% bupivacaine was added to Cip-18% [ P407-PBP ], respectively (fig. 15A and 15B). Limonene lowered the gelation temperature of Cip-18% [ P407-PBP ] by 14 deg.C, G' by 10.5kPa, and G "by 4.1kPa, so that they were very similar to Cip-3 CPE-18% [ P407-PBP ] (FIGS. 13D and 15B), indicating that the effect of CPE was mainly influenced by limonene. SDS lowered the gelation temperature of Cip-18% [ P407-PBP ] by about 1.5 ℃ but did not affect the plateau values for G' and G ". Bupivacaine has minimal effect on the mechanical properties and gelling temperature of Cip-18% [ P407-PBP ]. Injection of Cip-3 CPE-18% [ P407-PBP ] and Cip-3 CPE-15% [ P407-PBP ] is challenging. For example, Cip-3 CPE-15% [ P407-PBP ] is difficult to push through a No. 20 catheter and is expelled as a gel rather than a viscous liquid, which makes it difficult to place in vivo on the TM. Thus, for in vivo work, Cip-3 CPE-12% [ P407-PBP ] was chosen because its sol-gel transition is clear (G '> G' at body temperature; FIGS. 15C and 15D) and it does not gel after being expelled through a 20 gauge, 1.8 inch catheter at room temperature.
In vitro drug release and in vitro drug flux
The design of the formulation requires two components: CPE (8) which is expected to increase drug flux through the TM and hydrogels which are expected to slow flux but still prolong the duration of treatment required to clear the infection. The effect of hydrogel and 3CPE on ciprofloxacin transport rate was investigated by quantifying the following: 1) in vitro diffusion from a bulk hydrogel matrix (although it is unlikely to exist at the TM surface under infinite sink conditions); 2) ex vivo permeation through TM. In vitro release experiments showed that P407-PBP slowed drug release compared to the free drug solution (fig. 19). Introduction of 3CPE resulted in further slowing of drug release. However, the magnitude of ciprofloxacin released from Cip-3 CPE-18% [ P407-PBP ] was more than 30% greater than Cip-3 CPE-18% [ P407 ]. Drug transport across the TM was studied ex vivo in the auditory vesicles excised from healthy chinchillas described in the methods. Inclusion of 3CPE increased TM flux from a 1% ciprofloxacin solution by more than 4-fold and from Cip-18% [ P407-PBP ] by more than 10-fold (figure 16). Conversely, the presence of a hydrogel tends to reduce flux through the TM; this effect can be overcome by introducing CPE. The ex vivo model cannot be used to demonstrate the primary utility of hydrogels, which prolong the duration of drug flux through the TM by establishing a stable storage system, since the TM degrades after-48 hours at 37 ℃ due to microbial growth.
Tissue toxicity is a potentially important consideration, as CPE can disrupt the stratum corneum (28). The particular combination of 3CPE was chosen because it effectively enhances penetration and is non-toxic in vivo (see 8; Simons et al, Chemical specificity enhancers and in situ-forming respiratory drugs for trans-systemic drug delivery: progressive beyond Properties media (2008)). With 3- (4, 5-dimethyl-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole
Figure BDA0001614314770001151
The inner salt (MTS) assay assesses the cytotoxicity of polymer and 3CPE in three cell lines representing cell types in the auditory system: human dermal fibroblasts (hFB), PC12 cells (a pheochromocytoma cell line commonly used to test neurotoxicity), and normal adult primary epidermal keratinocytes from abdominal skin (fig. 20A). Use of LIVE-
Figure BDA0001614314770001152
The viatility/cytoxicity Kit was used as a confirmatory assay in hFB (FIG. 20B). The test formulations were placed in the upper chamber of a Transwell system with a pore size of 0.4 μm, with the cells placed below. P407-PBP itself showed little toxicity after 1 day, but showed considerable toxicity on day 3. The presence of 3CPE and ciprofloxacin increased cytotoxicity for all cell types and time points. However, in vivo biocompatibility is excellent: 200 μ L of Cip-3 CPE-18% [ P407-PBP ] was used ]The treated TM was histologically similar to a healthy TM that was not exposed to any treatment (fig. 17A). The gel adhered to the TM 7 days after application, but degraded completely within 3 weeks.
In vivo Performance in otitis media
OM induced by NTHi was established in chinchillas directly after inoculation into the middle ear, and then treated with 200 μ L of test material deposited onto the TM through the external auditory canal. In animals treated with 1% ciprofloxacin alone (n-8), NTHi was detectable in the middle ear fluid of 25% of the animals on day 1 and day 3, but cleared by day 7 only in 62.5% of the infected animals (fig. 18A; i.e. zero cfu [ colony forming units ] in the middle ear fluid aspirated from the dorsal side of the acinus, i.e. not passing the TM) with unacceptably low cure rates (31). Clearance was also low at 60% in animals with OM (n-5) treated with Cip-3 CPE-18% [ P407 ]. In contrast, 10 of the 10 animals treated with Cip-3 CPE-12% [ P407-PBP ] were cleared of OM within 24 hours after formulation application (FIG. 18A; P0.0065 by Fisher's exact test).
With Cip-3 CPE-12% [ P407-PBP ]]The 100% cure rate in treated animals can be explained by the time course of ciprofloxacin levels in the middle ear (fig. 18B). The concentration of ciprofloxacin peaked on day 1 (with Cip-3 CPE-12% [ P407-PBP ] ]39.1. mu.g mL in treated animals-14.2. mu.g mL in animals treated with 1% ciprofloxacin solution-1). Three days after administration of the formulation, the patient received Cip-3 CPE-12% [ P407-PBP%]The animals in (a) still had super-therapeutic ciprofloxacin in the middle ear (3.06. mu.g mL)-1) Whereas ciprofloxacin concentration dropped to zero in animals treated with the 1% ciprofloxacin solution. Minimum Inhibitory Concentration (MIC) of ciprofloxacin to NTHi is 0.1-0.5 mug mL-1(see Perez-V zquez et al, Antimicrob. Agents Chemother.47, 3539-3541 (2003); Hirakata et al, Antimicrob. Agents Chemother.53, 4225-4230 (2009)). 7 days after administration, with Cip-3 CPE-12% [ P407-PBP ]]The concentration of ciprofloxacin in the middle ear fluid of the treated animals was still 1.2. mu.g mL-1I.e. the antibiotic concentration in the blebs was higher than the MIC in this group over the entire 7 day period. No recurrence of OM was observed.
Considering TM for small molecules (e.g. CO)2And He) are relatively impermeable (12, 14, 34) and the otic topical antibiotic has been destroyed (e.g., with TM) onlyMyringotomy tube) was used for middle ear disease (Wall et al, pediatr. infection. dis. j.28, 141-. The effect of ciprofloxacin droplets in OM can be explained by the fact that: although also becoming thicker (fig. 17A), TM becomes more permeable 5-31 times to drug flux in OM (fig. 16).
Systemic distribution of ciprofloxacin
Ciprofloxacin was not detected in plasma samples of blood obtained in the transverse sinuses (table S2). Given this location close to the auditory bulb, the absence of ciprofloxacin indicates that no systemic exposure of the antibiotic has occurred.
Histological evaluation
Single dose treatment with Cip-3 CPE-12% [ P407-PBP ] was able to reverse the significant inflammatory response caused by NTHi and prevent bacterial growth (fig. 17B). At 7 days after administration of the formulation, the TM was excised intact within the tympanic membrane ring and processed into hematoxylin and eosin (H & E) stained sections. Normal chinchillas were consistently 10-20 μm thick (FIG. 17A). TM extracted 7 days after infection was approximately 5 times thicker (fig. 17A) and showed an acute inflammatory response with diffuse edema and dense infiltration of inflammatory cells. In contrast, TM treated with the gel formulation did not appear to be different from healthy TM, with a thickness of 10-20 μm (FIG. 17A). No tissue damage, necrosis or inflammatory cells were observed. These results demonstrate a benign tissue response to Cip-3 CPE-12% [ P407-PBP ].
Effect of Cip-3 CPE-12% [ P407-PBP ] on Hearing
The effect of Cip-3 CPE-12% [ P407-PBP ] on hearing sensitivity was assessed by auditory brainstem response (ABR; see methods; FIG. 18C). Placement of 200. mu.L of gel on the TM resulted in an ABR threshold of 16-24dB forward shift (hearing deterioration) to short and tone bursts at frequencies from 0.5Hz to 16kHz, averaging 18dB 8dB over the entire frequency. This slight hearing loss is comparable to the effects of cerumen (see Olusanya et al, Ann. trop. Paediatr.23, 121-.
Gel Properties of P407-PPE polymers
Compositions for testing were prepared by mixing 18% wt/vol P407-PBP polymer into a 1% wt/vol ciprofloxacin aqueous solution. The solution was stirred overnight and the following CPE was added: (a) 1% wt/vol Sodium Dodecyl Sulfate (SDS); (b) 2% wt/vol Limonene (LIM); (c) 0.5% wt/vol bupivacaine (Bup); or (d) 1% wt/vol SDS, 2% wt/vol LIM and 0.5% wt/vol Bup (3 CPE).
Measurement of shear rheology Using Linear Oscillating (100 rads)-11% strain, 1 ℃ min-1) The change in mechanical properties during the sol-gel transition was quantified. As shown in fig. 5. The storage (G') and loss (G ") moduli of the 18% P407 aqueous solutions at room temperature were about 0.1kPa, both showing a sharp increase in temperature range of 25-30 ℃ and then plateauing at about 6kPa and 4kPa, respectively. At temperatures below 27 ℃, G 'and G "remained close to within one standard deviation (as shown by the error bars), P407 behaves as a viscous liquid, while at temperatures above 28 ℃, G' became significantly larger than G", and P407 behaves solid-like. The inclusion of CPE (3CPE) in the P407 solution reduced the gelling process and rendered the delivery system ineffective. Specifically, the storage and loss moduli of the system remain less than 2kPa throughout the temperature range of 20-40 ℃. No crossover points were observed. The shear rheology results are consistent with our following findings in otoscopy: the P407-based gel disperses in the ear canal, resulting in poor adhesion to the TM. The gelling process took-20 seconds.
Figure 10 shows the rheological measurements of the P407-PBP composition. Linear oscillatory shear rheological measurements on 18% P407-PBP (100 rads)-11% strain, 1 ℃ min-1) Indicating that P407-PBP (containing 10mg ml)-1Ciprofloxacin) had storage (G') and loss (G ") moduli at room temperature of about 0.1 and 0.2kPa, respectively. Both G' and G "gradually increase over a temperature range of 27-38 deg.C, reaching plateaus at about 10 and 4kPa, respectively. At temperatures below 33 ℃, G "is greater than G ', the polymer solution behaves as a viscous liquid, while at temperatures above 33 ℃, G" is less than G', indicating solid-like behavior. The crossover point (33 ℃) is therefore the sol-gel transition temperature. Introduction of CPE in a composition of 1 wt% SDS, 2 wt% limonene and 0.5 wt% bupivacaine changed the rheology of P407-PBP. After the temperature has risen, G' and G"increased from near zero to 10 and 5kPa, respectively, at 22 ℃ and showed a crossover point (i.e., sol-gel transition) at 20 ℃. G 'continues to increase with temperature and reaches a plateau of 20kPa at body temperature, while G' starts to decrease at temperatures above 22 deg.C and reaches a plateau of 1kPa at body temperature. Further characteristics of the P407-PBP compositions with various penetration enhancers are given in Table E1.
TABLE E1 rheological Properties of exemplary P407-PBP compositions
Figure BDA0001614314770001181
Optimization of formulations
The standard formulation was defined as ciprofloxacin in 18% P407 with 1% SDS, 0.5% bupivacaine and 2% limonene. Starting from this formulation, others can optimize for gelling and mechanical properties as well as drug flux across chinchilla TM.
For example, an optimized formulation should produce a drug flux that results in a concentration within the receiving chamber of at least a minimum inhibitory concentration (MIC; a concentration that inhibits bacterial growth by 2 log units) within 12 hours. The MIC of ciprofloxacin of atypical haemophilus influenzae (NTHi) is less than 0.1-0.5, and that of streptococcus pneumoniae is 0.5-4 μ g/mL. [31, 32] for the optimized formulation, gelation should occur 10 seconds after application, yet be fluid at room temperature, and should provide a drug flux to reach MIC for 10 days per day. In vivo, the optimized formulation should eliminate infection in 100% of animals 5 days after treatment.
For optimization, two CPEs (different carbon chain lengths) can be analyzed from each of three main classes: anionic, cationic and nonionic (table 1). Other CPEs that may be included in the optimization experiment include: terpenes (such as limonene), benzalkonium chloride (antibacterial and antiseptic agents used in eye drops and nasal sprays, also as CPE), and bupivacaine (a potent local anesthetic, also as CPE). Bupivacaine can also be used as an additional therapeutic agent to treat pain from OM.
TABLE E2 characterization of surfactant Chemical Penetration Enhancers (CPE)
CPE Categories M.W. Carbon chain length
Sodium octyl sulfate Anion(s) 232 8
Sodium dodecyl sulfate Anion(s) 288 12
Octyl-trimethyl-ammonium bromide Cation(s) 252 8
Dodecyl-trimethyl-ammonium bromide Cation(s) 308 12
Tween 20 Non-ionic 1228 12
Tween 80 Non-ionic 1310 17
Antibiotics can be selected based on clinical criteria (antimicrobial profile, current practice; i.e., transformability), efficacy, solubility in the delivery vehicle, stability at 37 ℃, and other physicochemical parameters. The default antibiotic is ciprofloxacin, since (a) it is small (331Da), moderately hydrophobic (log P ═ 0.28), and can be dissolved in aqueous solutions at acidic pH (pK) at relatively high concentrations (pK)a6.16) and has a broad antimicrobial spectrum; (b) it is currently used clinically to treat acute otorrhea in children through tympanostomy tubes.
To minimize animal experiments, chinchilla TM can only be used to achieve sufficient flux of CPE in initial screening on cadaveric skin (HES). Since flux across the TM may be greater than across the HES, screening may also increase the likelihood of success of the formulation in an in vivo model of downstream OM. Integrity of human cadaver skin and chinchilla TM samples can be verified by electrical impedance measurements. HES can be tested in Franz diffusion cells; chinchilla TM in 12-well plates. For each drug, the flux was measured at the maximum concentration that can be dissolved in the formulation. The flux of the drug or CPE can be measured by HPLC with appropriate detection.
Single CPE
For each CPE, ciprofloxacin flux can be measured across the HES, measuring flux over the following concentration ranges: starting at half the concentration that appears to be effective in transdermal application [26a ], increases in the same increments (or multiples thereof) until a sufficient concentration is reached. The results of promising CPE in HES testing can be confirmed in chinchilla TM prior to additional experiments. The experiment can be repeated with different therapeutic agents other than ciprofloxacin.
Cooperative CPE
Between CPEThe synergy of (a) was formally demonstrated by isobolographic analysis (fig. 6). For the two single enhancers that produced the greatest increase in flux, the concentrations (EC) that both resulted in 50% of the greatest increase in flux were determined50). If both are from the same class of enhancer, the next best from the other class of agent is also tested, since synergy typically occurs in the process of acting through different mechanisms on a common phenomenon. Synergy (as well as additivity and antagonism) can then be demonstrated by constructing an isobologram (figure 6). EC (EC)50Values can be determined by logistic analysis using stat software (stat Corporation, College Station, TX).
The anesthetic permeation enhancer may enhance the enhancement of drug flux by the surfactant and the terpene permeation enhancer. For example, bupivacaine can potentiate the increase in drug flux by SDS and limonene (see fig. 21).
Flux of antibiotics
In vivo studies may be initially performed with ciprofloxacin. However, other antibiotics can also be studied to assess trans-tympanic drug diffusion as a function of drug properties. Antibiotics commonly used to treat otitis media can be studied, or can be used to treat OM if systemic distribution and toxicity associated with oral delivery are not an issue. Target organisms include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Criteria for evaluating successful drug candidates include solubility, stability, physicochemical properties, efficacy, and systemic toxicity. The nature of the TM may also affect which drug works best. Candidates after ciprofloxacin include other quinolones with better gram-positive coverage, higher potency or less protein binding (e.g. levofloxacin and moxifloxacin) or broad spectrum agents such as carbapenems (e.g. meropenem). Drugs with significant ototoxicity (e.g., vancomycin) were not studied.
For the antibiotic levofloxacin, trans-tympanic permeation of the levofloxacin formulation (1.5% levofloxacin in water and 1.5% levofloxacin with permeation enhancer and matrix former) is shown compared to the ciprofloxacin formulation in fig. 22 (B).
A panel of antibiotics, selected for a range of physicochemical properties, is listed in table 2. The following additional therapeutic agents may also be studied in combination with antibiotic candidates: (a) dexamethasone, which is used clinically in combination with antibiotics, (2) beta-lactamase inhibitors, such as clavulanate and tazobactam.
TABLE E3. antibiotic Properties of therapeutic Agents used as compositions
Antibiotics Categories M.W. Log P
Amoxicillin Penicillin 365 0.87
Azithromycin Macrolides 749 4.02
Cefuroxime Cephalosporin 2 nd generation 424 -0.16
Ceftriaxone Cephalosporin of 3 rd generation 555 -1.47
Trimethoprim Diaminopyrimidines 290 0.91
Ciprofloxacin Quinolones 331 0.28
More than one antibiotic used in combination may also be tested if a single antibiotic provides insufficient flux or fails to reach the MIC. A synergistic drug combination may allow for an increased flux of antibacterial efficacy (peak effect) for a given total drug mass. The same statistical approach as for CPE can be used to study synergy.
Encapsulation of bupivacaine
Bupivacaine differs from other CPEs in that it has a solid (free base) form. This provides the opportunity to extend the duration of CPE effect (if desired) by sustained release from the drug delivery composition. The bupivacaine-releasing particles may be suspended in the formulation. Experiments may be required to verify that bupivacaine levels are not elevated to neurotoxic levels in the middle or inner ear.
Measurement of drug flux through human skin
Heat-shed epidermis (HES) with stratum corneum can be prepared from fresh frozen, full-thickness, glabrous human abdominal skin (National Disease Research exchange, philiadelphia, PA). [38] HES was immobilized between the wells of a vertical (Franz) diffusion cell (Permegagear, Bethlehem, Pa.). At fixed time points, samples were removed from the receiving chamber and analyzed by HPLC.
Ex vivo measurement of flux using tympanic membrane
The TM within the external ear canal and tympanic membrane ring is separated integrally from the skull. The pellet (blob), which will serve as the donor chamber, was placed in a 12-well plate and pre-incubated for 15 minutes at 37 ℃. Add 200 μ Ι _ of test solution to the donor chamber. At a fixed point in time, the receiving medium is removed. Drug concentrations were quantified by reverse phase HPLC (1100 series, Agilent Technologies, Palo Alto, CA).
Determining integrity of HES and TM
Electrical impedance measurements can be used to assess the integrity of skin and TM samples. [39]Initial resistivity (resistance x exposed area) of < 35kOhm x cm, respectively2And < 18kOhm cm2The skin sample and TM are considered damaged.
Hydrogel formulations
Hydrogels can be prepared by adding polymer powder to the drug-CPE aqueous solution. Gels of different weight percentages (5% -20%) of P407-PPE (co-poloxamer 407/polyphosphate) were prepared by simple dissolution. An in situ covalently cross-linked polymer (1-10% by weight) can be synthesized, [25] dissolved in an antibiotic-CPE solution and delivered in separate barrels of a dual barrel syringe.
Examples of Synthesis of P407-PPE polymers
The phosphate ester precursor (e.g., a compound of formula (a)) can be prepared by a condensation reaction of 2-chloro-2-oxo-1, 3, 2-dioxaphospholane (COP) and an alcohol (e.g., Y-OH, where Y is defined herein), then purified by vacuum distillation, and analyzed by proton and phosphorus NMR spectroscopy. Hydrophobic P407-PPE polymers (PPE-P407-PPE) may be synthesized by ring-opening polymerization (ROP) of a phosphate ester with P407 in the presence of an organic catalyst, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), at-20 ℃. After the reaction was complete (complete consumption of monomer was confirmed by NMR spectroscopy), an excess of acetic acid in Dichloromethane (DCM) was added to the reaction mixture to quench the reaction. The product can be purified by precipitation in ether (3 times) and dried under vacuum to a white powder. Proton and phosphorus NMR spectroscopy, fourier transform infrared spectroscopy, and gel permeation chromatography were used to characterize the polymer and confirm its purity.
Gelation temperature and time, gel rheology
The storage and loss moduli may be measured every 1 ℃ during a temperature sweep from 0 ℃ to 40 ℃. The temperature at which the storage modulus exceeds the loss modulus is considered the gelation temperature. To measure gel time, the formulation in the scintillation vial was immersed in a 37 ℃ water bath on a stir plate. The time at which the stir bar stopped rotating was recorded as the gel time.
Kinetics of in vitro Release
Drug and/or CPE release from the formulation can be assessed by placing the gel in a low molecular weight cut-off (Transwell) insert (PBS below) in a 12-well plate. At fixed time points (0.5, 1, 2, 6, 24, 48, 120h), samples of PBS from the receiving chamber were taken and analyzed for drug and/or CPE levels by HPLC or other analytical techniques.
Cytotoxicity test
Cytotoxicity can be determined for the cell types present in the tympanic membrane and the wall surrounding the outer ear. These cell types include keratinocytes, fibroblasts, and PC12 cells (a pheochromocytoma cell line commonly used to study neurotoxicity). Cells were exposed to a range of concentrations of drug, CPE and gel components. For CPE, the upper initial concentration limit is set by the published skin toxicity value. For drugs, the upper limit is set by the solubility in the test formulation. Cytotoxicity was assessed using the MTT assay, which is widely used for cytotoxicity screening, between 1 and 10 days of exposure to the test components. Since it can reflect cell proliferation, a standard live-dead assay was used as a confirmation test. [50]
Biocompatibility testing
Formulations that show cell viability in excess of 80% will be tested in vivo. Mu.l of the test solution was instilled onto chestnut rats TM under isoflurane oxygen anesthesia. One, four, ten and thirty days later, the animals were euthanized for otoscopy and histological analysis of TM and outer ear, noting substance residues (and their adhesion to TM), inflammation, TM thickening, middle ear exudate and tissue damage. The point in time will allow analysis of the duration of the preparation in the ear canal. The incision was made as for TM removal, but the outer and middle ear were removed in their entirety and demineralized for subsequent sectioning and processed into hematoxylin-eosin stained sections using standard procedures. Electron microscopy of inner ear structures can also be performed to assess ototoxicity.
Biological membrane
In vitro studies of the effect of formulation components on biofilm formation can be performed as an adjunct to observations obtained in vivo models. The formed biofilm can be exposed to concentrations corresponding to the dose-response curves of all diffusible components (drug, CPE, hydrogel precursors) of the formulation (alone and in combination) and evaluated for changes in morphology and bacterial populations. Similar studies can be performed to assess the ability of the components to prevent biofilm formation and disrupt inactivated biofilms in vitro.
Bacterial colonies were suspended in medium and OD was added490Adjusted to 0.65, then diluted 1: 6 and brought to 37 ℃ with 5% CO2Incubate for about 3 hours to reach mid-log phase. [30]The suspension was then diluted 1: 2500 in culture medium, 200. mu.L was placed into each well of an 8-well chamber slide, and incubated at 37 ℃ with 5% CO2The incubation was continued for about 16 hours. The medium was changed every 12 hours (taking care not to disrupt the biofilm) until the desired biofilm thickness was reached. The samples were then fixed and stained with a live-dead assay. Biofilm thickness and bacterial survival can be quantified by confocal microscopy and further characterized by SEM images and/or immunohistochemical methods.
In vivo chinchilla test
To determine the efficacy of the antimicrobial hydrogel in vivo, the formulation can be applied to the TM of chinchilla having an OM. The test compositions were placed in the left ear of the animal the right ear was used for control (no treatment, CPE only, gel only, etc.) in selected experiments, the middle ear fluid can be sampled to track the bactericidal effect and flux of antibiotics and CPE.
Animals were challenged by direct inoculation of 25-100cfu into the middle ear through the upper bleb. After 48-96 hours, infection was confirmed by: (a) otoscopy and tympanometry, (b) culture of middle ear fluid through a 3-5mm opening in the alveolar bone (performed under ketamine/xylazine anesthesia); results were returned overnight. According to our experience, almost all animals develop disease after direct vaccination. In the case of animals that did not develop disease, they were excluded from the study. Once the presence of otitis media was confirmed, the hydrogel was applied to lateral chestnut rats under ketamine/xylazine anesthesia.
To assess biofilm, the middle ear mucosa is visualized [52], and tissue samples from animals are analyzed by Scanning Electron Microscopy (SEM) to detect biofilm and by live-dead staining to detect viable bacteria therein. [21] Immunohistochemistry of bacteria can be used as a confirmatory test. These data will allow the determination of the effect of multiple experimental groups on biofilm formation. The effect of CPE without antibiotics on biofilm formation in OM can also be studied.
For prophylactic studies, strategies designed to mimic the pathogenesis of disease in children, inducing experimental otitis media, where it was observed that post-colonization viral respiratory infections lead to negative middle ear pressure, can be used. Using a small size vascular catheter 10 7-108cfu bacteria were inoculated into the nasopharynx of chinchillas. After 24 hours, nasopharyngeal colonization was confirmed by quantitative culture. [29g, 51 ]]The gel was placed in the left external ear canal (in contact with the TM). At 48 hours after gel application, barotrauma was introduced by placing a 25 gauge needle in the middle ear (through the upper bleb) and aspirating 500 μ L of air while performing tympanometry for anesthesia to record the presence of negative middle ear pressure within the middle ear cavity. This creates a negative pressure that lasts for hours and induces the bacterial otopathogen to climb the eustachian tube into the middle ear. The animals OM were observed daily for development and if a change in TM was observed, the culture was performed. (if no change was observed, culture was performed 3-4 days after barotrauma to confirm the absence of culture positive disease).
In both cases, 0.2mL of the test composition (hydrogel with drug and CPE) was applied to the TM under otoscopy via a syringe with attached vascular catheter. The entire surface of the TM was coated. Clinical examinations were performed as above and/or 1, 3, 5 and 7 days after drug administration to monitor disease. Otoscopy is used to track contact of the hydrogel with the TM. Every other day, middle ear fluid (if present) was collected via a vascular catheter inserted through an incision made under sterile conditions during initial culture confirmation. In the absence of middle ear fluid, lavage was performed with 500 μ LHanks solution and withdrawn through the vascular catheter. Quantification of the middle ear broth culture was performed by 10-fold dilution of middle ear broth and incubation for 16 hours at 37 ℃.
The level of drug in the middle ear can be confirmed by: (a) methanol was added to the middle ear broth until all proteins precipitated, (b) centrifuged to remove any precipitated proteins and cell debris, and (c) analyzed by HPLC.
Less than 2mL of blood can be collected by specific interval superior sagittal sinus puncture after starting treatment to measure systemic (plasma) drug concentrations. Blood (≦ 2mL) was drawn from animals whose formulations had been deposited in the ear for biocompatibility testing or OM model by superior sagittal sinus puncture, immediately placed on ice, and plasma was separated by centrifugation. The samples will be stored at-20 ℃ and subsequently antibiotic and/or CPE concentrations measured. Levels after days 1, 4 and 10 provide a useful survey of the median course of treatment.
Auditory brain response
Hearing impairment can be caused by the conductive effect of the gel (conductive effect) or by direct toxicity to the middle or inner ear. It is difficult to predict in advance the thickness of the formulation of the final therapeutic system to be applied in humans. Prior to the measurement of the Auditory Brain Response (ABR), a thickness range of 100 μm to 500 μm was applied, which completely filled the auditory canal of chinchillas. To identify possible ototoxic effects, the test was repeated after removing the gel (by rinsing and/or scraping depending on consistency).
ABR experiments were performed using a custom designed system built around National Instruments (Austin, TX) software (Lab View) and hardware (including GPIB controller and ADC board). The custom LabView program calculates the stimuli and downloads them to a programmable stimulus generator (Hewlett Packard 33120A). The stimuli were then filtered and attenuated by an anti-aliasing filter (Krohnhhite 3901) (Tucker-Davis Technologies). The 2 ADC channels sample the amplified ABR signal and microphone output sealed in the animal ear canal while stimulating the output.
The sound stimulus is a 20ms tone burst pair of opposite polarity. The frequency of the bursts will increase from 500Hz to 16kHz in octave steps. Each burst is a sinusoidal window with 40ms between the two bursts. The responses of ABR to 250 stimulus pairs will be averaged at each stimulus level. The ABR response will be calculated from the sum of the average responses for the two different polarities. The stimulation level will vary at a 10dB step. The visual judgment of the threshold at each stimulation frequency will be determined after the measurement in a blinded manner.
The reduced stimulation was played through a hearing aid earpiece placed in the intact ear canal of adult male chinchillas (400-. The headphone coupler includes a microphone that monitors the level of acoustic stimulation. The ABR obtained in the sound attenuation cell will be measured with a differential amplifier with a gain of 10,000 and a measurement bandwidth of 100Hz to 3 kHz. The measurement results are obtained from the positive electrode in the muscle behind the tested ear; the negative electrode is located at the cranial crown and the ground electrode is located behind the opposite ear.
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In the claims, an indefinite article "a" or "an" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include an "or" between one or more members of a group are deemed to satisfy one, more than one, or all of the group members if present, used, or otherwise associated in a given product or process, unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one group member is present, used, or otherwise associated in a given product or process. The invention includes embodiments in which more than one, or all of the group members are present, used, or otherwise associated in a given product or process.
Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that references another claim may be amended to include one or more limitations found in any other claim that references the same base claim. Where elements are represented in lists (e.g., in markush group format), each subgroup of elements is also disclosed, and any element can be removed from the group. It will be understood that, in general, where the invention or aspects of the invention are referred to as including particular elements and/or features, certain embodiments of the invention or aspects of the invention consist of, or consist essentially of, such elements and/or features. For simplicity, these embodiments are not specifically set forth herein. It should also be noted that the terms "comprising" and "comprises" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Moreover, unless otherwise indicated or otherwise evident from the context or understanding of one of ordinary skill in the art, values expressed as ranges can assume any specific value or sub-range within the stated range, up to the tenth of the unit of the lower limit of the range, in different embodiments of the invention, unless the context clearly dictates otherwise.
This application is related to a number of issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, the specification shall control. Furthermore, any particular embodiment of the present invention that is prior art may be explicitly excluded from any one or more claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if exclusion is not explicitly recited herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the presence of prior art.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited by the above description, but rather is as set forth in the following claims. It will be understood by those of ordinary skill in the art that various changes and modifications may be made to the present description without departing from the spirit or scope of the present invention as defined in the following claims.

Claims (54)

1. A composition comprising:
(a) antibiotics or combinations of antibiotics, wherein each antibiotic is a beta-lactamase inhibitor or an antibiotic with a molecular weight of 290g/mol to 749 g/mol;
(b) a penetration enhancer or combination of penetration enhancers comprising one or more of: sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethyl ammonium bromide, cetyl pyridinium chloride
Figure FDA0003540956370000011
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl chembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure FDA0003540956370000012
Dodecyl pyridine chloride
Figure FDA0003540956370000014
Cetyl pyridinium chloride
Figure FDA0003540956370000013
Benzyl dimethyldodecylammonium chloride, benzyl dimethylmyristylammonium chloride, benzyl dimethylstearoylammonium chloride, octyl trimethylammonium bromide, dodecyltrimethylammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80; limonene, cymene, pinene, camphor, menthol, complene, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, beta-caryophyllene, eucalyptol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebacate, glycerol monolaurate, glycerol monooleate, or ethylpiperazine carboxylate; sodium lauroyl sarcosinate, sorbitan monooleate, octoxynol-9, diethyl sebacate, sodium polyacrylate with molecular weight of 2500000MW, and octyldodecanol; pyrrolidone, bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomecaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticarcine, etidocaine, mepivacaine, piperocaine, or tricaine, wherein the permeation enhancer or combination of permeation enhancers increases the flux of the antibiotic or combination of antibiotics across the barrier; and
(c) A matrix-forming agent or a combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a polymer;
wherein:
the composition forms a gel at a temperature above the phase transition temperature; and is
The phase transition temperature is lower than 37 ℃;
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus 5 ℃;
(ii) (ii) the storage modulus of the composition is greater than 15% or greater than 500Pa, whichever is less, of the storage modulus of the reference composition at a temperature of 37 ℃; and
(iii) (ii) the loss modulus of the composition is from 15% to 150% of the loss modulus of the reference composition at a temperature of 37 ℃;
wherein the reference composition is the composition in the absence of the penetration enhancer or combination of penetration enhancers;
wherein the polymer is of formula (I'):
Figure FDA0003540956370000021
wherein:
y is independently for each occurrence optionally substituted C1-6An alkyl group;
R3each occurrence is independently optionally substituted C1-6An alkyl group;
G1Aand G2AEach independently is hydrogen; and is
p, q, r, s and t are each independently integers, inclusive, from 1 to 200, where the sum of p and t is at least 1 and the sum of q, r and s is at least 1;
Wherein when each of the above alkyl groups is substituted at a carbon atom with one or more substituents, the one or more substituents at that carbon atom are independently selected from the substituents in group (i):
group (i) consists of: halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)(Raa)2、-P(＝O)(ORcc)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)(N(Rbb)2)2、-OP(＝O)(N(Rbb)2)2、-NRbbP(＝O)(Raa)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(N(Rbb)2)2、-P(Rcc)2、-P(ORcc)2、-P(Rcc)3 +X-、-P(ORcc)3 +X-、-P(Rcc)4、-P(ORcc)4、-OP(Rcc)2、-OP(Rcc)3 +X-、-OP(ORcc)2、-OP(ORcc)3 +X-、-OP(Rcc)4、-OP(ORcc)4、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups; wherein X-Is a counter ion;
or two pairs of hydrogen on carbon atoms by groups ═ O, ═ S, ═ NN (R)bb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbbOr as NORccReplacement;
Raaeach instance of (A) is independently selected from C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RaaThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5R ddSubstituted by groups;
wherein:
Rbbeach instance of (A) is independently selected from hydrogen, -OH-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)(Raa)2、-P(＝O)(ORcc)2、-P(＝O)(N(Rcc)2)2、C1-10 alkyl, C1-10 perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RbbThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups; wherein X-is a counterion;
Rcceach instance of (A) is independently selected from hydrogen, C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstitution of radicals;
Rddeach instance of (A) is independently selected from halogen, -CN, -NO2、-N3、-SO2H、-SOaH、-OH、-ORee、-ON(Rff)2、-N(Rff)2、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)(ORee)2、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C 2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RggSubstituted by radicals, or two pairs of RddSubstituents may be linked to form ═ O or ═ S; wherein X-Is a counter ion;
Reeeach of (1)Each instance is independently selected from C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, C6-10Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RggSubstituted by groups;
Rffeach instance of (A) is independently selected from hydrogen, C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, or two RffThe groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5R ggSubstituted by groups; and is provided with
RggEach instance of (A) is independently halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6Alkyl, -ON (C)1-6Alkyl radical)2、-N(C1-6Alkyl radical)2、-N(C1-6Alkyl radical)3 +X-、-NH(C1-6Alkyl radical)2 +X-、-NH2(C1-6Alkyl radical)+X-、-NH3 +X-、-N(OC1-6Alkyl) (C1-6Alkyl), -N (OH) (C)1-6Alkyl), -NH (OH), -SH, -SC1-6Alkyl, -SS (C)1-6Alkyl), -C (═ O) (C)1-6Alkyl), -CO2H、-CO2(C1-6Alkyl), -OC (═ O) (C)1-6Alkyl), -OCO2(C1-6Alkyl), -C (═ O) NH2、-C(＝O)N(C1-6Alkyl radical)2、-OC(＝O)NH(C1-6Alkyl), -NHC (═ O) (C)1-6Alkyl), -N (C)1-6Alkyl) C (═ O) (C)1-6Alkyl), -NHCO2(C1-6Alkyl), -NHC (═ O) N (C)1-6Alkyl radical)2、-NHC(＝O)NH(C1-6Alkyl), -NHC (═ O) NH2、-C(＝NH)O(C1-6Alkyl), -OC (═ NH) (C)1-6Alkyl), -OC (═ NH) OC1-6Alkyl, -C (═ NH) N (C)1-6Alkyl radical)2、-C(＝NH)NH(C1-6Alkyl), -C (═ NH) NH2、-OC(＝NH)N(C1-6Alkyl radical)2、-OC(NH)NH(C1-6Alkyl), -OC (NH) NH2、-NHC(NH)N(C1-6Alkyl radical)2、-NHC(＝NH)NH2、-NHSO2(C1-6Alkyl), -SO2N(C1-6Alkyl radical)2、-SO2NH(C1-6Alkyl), -SOgNH2、-SO2C1-6Alkyl, -SO2OC1-6Alkyl, -OSO2C1-6Alkyl, -SOC1-6Alkyl, -Si (C)1-6Alkyl radical)3、-OSi(C1-6Alkyl radical)3-C(＝S)N(C1-6Alkyl radical)2、C(＝S)NH(C1-6Alkyl), C (═ S) NH2、-C(＝O)S(C1-6Alkyl), -C (═ S) SC1-6Alkyl, -SC (═ S) SC1-6Alkyl, -P (═ O) (OC)1-6Alkyl radical)2、-P(＝O)(C1-6Alkyl radical)2、-OP(＝O)(C1-6Alkyl radical)2、-OP(＝O)(OC1-6Alkyl radical)2、C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, C6-10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two paired RggSubstituents may be linked to form ═ O or ═ S; wherein X-Is a counter ion.
2. The composition of claim 1, wherein:
satisfying at least one of conditions (i), (ii), and (iii):
(i) the phase transition temperature of the composition is less than the phase transition temperature of the reference composition plus 5 ℃;
(ii) (ii) the storage modulus of the composition is greater than 15% of the storage modulus of the reference composition at a temperature of 37 ℃; and
(iii) the loss modulus of the composition is 80% to 120% of the loss modulus of the reference composition at a temperature of 37 ℃.
3. The composition of claim 1, wherein the storage modulus is greater than 50% of the storage modulus of the reference composition at a temperature of 37 ℃; or wherein the phase transition temperature of the composition is lower than the phase transition temperature of the reference composition; and/or wherein the phase transition temperature is above 10 ℃.
4. The composition of claim 3, wherein the storage modulus is greater than 70% of the storage modulus of the reference composition at a temperature of 37 ℃.
5. The composition of claim 3, wherein the storage modulus is greater than 80% of the storage modulus of the reference composition at a temperature of 37 ℃.
6. The composition of claim 3, wherein the storage modulus is greater than 90% of the storage modulus of the reference composition at a temperature of 37 ℃.
7. The composition of claim 3, wherein the storage modulus is greater than 100% of the storage modulus of the reference composition at a temperature of 37 ℃.
8. The composition of claim 3, wherein the composition has a phase transition temperature greater than 20 ℃.
9. The composition of claim 8, wherein the composition has a phase transition temperature greater than 30 ℃.
10. The composition of claim 1, wherein the composition comprises at least 0.5% weight/volume penetration enhancer.
11. The composition of claim 10, wherein the composition comprises at least 1% weight/volume penetration enhancer.
12. The composition of claim 10, wherein the composition comprises at least 2% weight/volume penetration enhancer.
13. The composition of claim 10, wherein the composition comprises at least 3% weight/volume penetration enhancer.
14. The composition of claim 10, wherein the composition comprises at least 4% weight/volume penetration enhancer.
15. The composition of claim 10, wherein the composition comprises at least 5% weight/volume penetration enhancer.
16. The composition of claim 10, wherein the composition comprises at least 6% weight/volume penetration enhancer.
17. The composition of claim 10, wherein the composition comprises at least 7% weight/volume penetration enhancer.
18. The composition of claim 10, wherein the composition comprises at least 8% weight/volume penetration enhancer.
19. The composition of claim 1, wherein the polymer is of the formula:
Figure FDA0003540956370000071
20. the composition of claim 1, wherein the polymer is of the formula:
Figure FDA0003540956370000072
21. the composition of claim 1, wherein the penetration enhancer is selected from the group consisting of sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, cetyl trimethylammonium bromide, cetyl pyridinium chloride
Figure FDA0003540956370000075
Benzethonium chloride, cocamidopropyl betaine, cetyl alcohol, oleyl alcohol, octyl glucoside, decyl maltoside, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium heptadecyl sulfate, sodium eicosyl sulfate, nicotine sulfate, sodium taurocholate sulfate, dimethyl sulfoxide, sodium tridecyl phosphate; decyl dimethyl ammonium propane sulfonate, oleyl chembetine, myristyl dimethyl ammonium propane sulfonate; chlorinated benzylpyridines
Figure FDA0003540956370000073
Dodecyl pyridine chloride
Figure FDA0003540956370000074
Cetyl pyridinium chloride
Figure FDA0003540956370000081
Benzyl dimethyl dodecyl ammonium chloride, benzyl dimethyl myristyl ammonium chloride, benzyl dimethyl stearyl ammonium chloride, octyl trimethyl ammonium bromide, dodecyl trimethyl ammonium chlorideAlkylammonium bromide, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80; limonene, cymene, pinene, camphor, menthol, camphor, phellandrene, sabinene, terpinene, borneol, eucalyptol, geraniol, linalool, piperitone, terpineol, eugenol acetate, safrole, benzyl benzoate, lupinene, beta-caryophyllene, bupivacaine, tetracaine, procaine, proparacaine, propoxycaine, dicaine, cyclomecaine, chloroprocaine, benzocaine, lidocaine, prilocaine, levobupivacaine, ropivacaine, dibucaine, articaine, ticaine, etidocaine, mepivacaine, piperocaine, and trimetaine.
22. The composition of claim 21, wherein the penetration enhancer is limonene, and the composition comprises 1.5% to 3% limonene by weight.
23. The composition of claim 22, wherein the penetration enhancer is a combination of sodium lauryl sulfate, limonene, and bupivacaine.
24. The composition of claim 1, wherein the antibiotic agent is selected from the group consisting of: ciprofloxacin, cefuroxime, cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefbuntan, ceftizoxime, ceftriaxone, cefepime, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin.Forest, oxacillin, penicillin, piperacillin, ticarcillin, mafenide, sulfacetamide, sulfamethylthiadiazole, sulfasalazine, and sulfadiazine
Figure FDA0003540956370000082
Azole, trimethoprim and trimethoprim-sulfamethoxazole
Figure FDA0003540956370000083
And (3) azole.
25. The composition of claim 1, further comprising an additional therapeutic agent selected from the group consisting of: (i) an anesthetic; (ii) an anti-inflammatory agent; (iii) a beta-lactamase inhibitor; and (iv) steroids.
26. The composition of claim 25, wherein the anesthetic is bupivacaine.
27. The composition of claim 25, wherein the anti-inflammatory agent is dexamethasone.
28. The composition of claim 1, wherein p and t are each integers from 1 to 100, inclusive.
29. The composition of claim 1, wherein p and t are each integers from 1 to 10, inclusive.
30. The composition of claim 1, wherein r is an integer from 10 to 100, inclusive.
31. The composition of claim 1, wherein R3Is methyl.
32. The composition of claim 1, wherein at least one occurrence of Y is butyl.
33. A matrix-forming agent or combination of matrix-forming agents, wherein the matrix-forming agent or combination of matrix-forming agents comprises a polymer of formula (Γ):
Figure FDA0003540956370000091
wherein:
y is independently for each occurrence optionally substituted C 1-6An alkyl group;
R3each occurrence is independently optionally substituted C1-6An alkyl group;
G1Aand G2AEach independently is hydrogen; and is
p, q, r, s and t are each independently integers, inclusive, from 1 to 200, where the sum of p and t is at least 1 and the sum of q, r and s is at least 1; the matrix forming agent forms a gel at a temperature above the phase transition temperature; and is
The phase transition temperature is lower than 37 ℃;
and at least one of conditions (i), (ii), and (iii) is satisfied:
(i) the phase transition temperature of the composition comprising the matrix former or combination of matrix formers is less than the phase transition temperature of a reference composition plus 5 ℃;
(ii) (ii) the storage modulus of the composition is greater than 15% of the storage modulus of the reference composition at a temperature of 37 ℃; and
(iii) (ii) the loss modulus of the composition is 80% to 120% of the loss modulus of the reference composition at a temperature of 37 ℃;
wherein the reference composition is the composition in the absence of a penetration enhancer or combination of penetration enhancers;
wherein when each of the above alkyl groups is substituted at a carbon atom with one or more substituents, the one or more substituents at that carbon atom are independently selected from the substituents in group (i):
Group (i) consists of: halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)(Raa)2、-P(＝O)(ORcc)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)(N(Rbb)2)2、-OP(＝O)(N(Rbb)2)2、-NRbbP(＝O)(Raa)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(N(Rbb)2)2、-P(Rcc)2、-P(ORcc)2、-P(Rcc)3 +X-、-P(ORcc)3 +X-、-P(Rcc)4、-P(ORcc)4、-OP(Rcc)2、-OP(Rcc)3 +X-、-OP(ORcc)2、-OP(ORcc)3 +X-、-OP(Rcc)4、-OP(ORcc)4、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups; wherein X-Is a counter ion;
or two pairs of hydrogen on a carbon atom are substituted by groups ═ O, ═ S, ═ NN (R)bb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbbOr as NORccReplacement;
Raaeach instance of (A) is independently selected from C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RaaThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups;
wherein:
Rbbeach instance of (A) is independently selected from hydrogen, -OH, -ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)(Raa)2、-P(＝O)(ORcc)2、-P(＝O)(N(Rcc)2)2、C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C 1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RbbThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups; wherein X-Is a counter ion;
Rcceach instance of (A) is independently selected from hydrogen, C1-10Alkyl radical, C1-10Perhaloalkyl, C2-10Alkenyl radical, C2-10Alkynyl, hetero C1-10Alkyl, hetero C2-10Alkenyl, hetero C2-10Alkynyl, C3-10Carbocyclyl, 3-14 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, or two RccThe groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RddSubstituted by groups;
Rddis independently selected fromHalogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)(ORee)2、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5R ggSubstituted by radicals, or two pairs of RddThe substituents may beLinked to form either O or S; wherein X-Is a counter ion;
Reeeach instance of (A) is independently selected from C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, C6-10Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RggSubstituted by groups;
Rffeach instance of (A) is independently selected from hydrogen, C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, or two RffThe groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5RggSubstituted by groups; and is
RggEach instance of (A) is independently halogen, -CN, -NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6Alkyl, -ON (C)1-6Alkyl radical)2、-N(C1-6Alkyl radical)2、-N(C1-6Alkyl radical)3 +X-、-NH(C1-6Alkyl radical)2 +X-、-NH2(C1-6Alkyl radical)+X-、-NH3 +X-、-N(OC1-6Alkyl) (C1-6Alkyl), -N (OH) (C) 1-6Alkyl), -NH (OH), -SH, -SC1-6Alkyl, -SS (C)1-6Alkyl), -C (═ O) (C)1-6Alkyl), -CO2H、-CO2(C1-6Alkyl), -OC (═ O) (C)1-6Alkyl), -OCO2(C1-6Alkyl), -C (═ O) NH2、-C(＝O)N(C1-6Alkyl radical)2、-OC(＝O)NH(C1-6Alkyl), -NHC (═ O) (C)1-6Alkyl), -N (C)1-6Alkyl) C (═ O) (C)1-6Alkyl), -NHCO2(C1-6Alkyl), -NHC (═ O) N (C)1-6Alkyl radical)2、-NHC(＝O)NH(C1-6Alkyl), -NHC (═ O) NH2、-C(＝NH)O(C1-6Alkyl), -OC (═ NH) (C)1-6Alkyl), -OC (═ NH) OC1-6Alkyl, -C (═ NH) N (C)1-6Alkyl radical)2、-C(＝NH)NH(C1-6Alkyl), -C (═ NH) NH2、-OC(＝NH)N(C1-6Alkyl radical)2、-OC(NH)NH(C1-6Alkyl), -OC (NH) NH2、-NHC(NH)N(C1-6Alkyl radical)2、-NHC(＝NH)NH2、-NHSO2(C1-6Alkyl), -SO2N(C1-6Alkyl radical)2、-SO2NH(C1-6Alkyl), -SO2NH2、-SO2C1-6Alkyl, -SO2OC1-6Alkyl, -OSO2C1-6Alkyl, -SOC1-6Alkyl, -Si (C)1-6Alkyl radical)3、-OSi(C1-6Alkyl radical)3-C(＝S)N(C1-6Alkyl radical)2、C(＝S)NH(C1-6Alkyl), C (═ S) NH2、-C(＝O)S(C1-6Alkyl), -C (═ S) SC1-6Alkyl, -SC (═ S) SC1-6Alkyl, -P (═ O) (OC)1-6Alkyl radical)2、-P(＝O)(C1-6Alkyl radical)2、-OP(＝O)(C1-6Alkyl radical)2、-OP(＝O)(OC1-6Alkyl radical)2、C1-6Alkyl radical, C1-6Perhaloalkyl, C2-6Alkenyl radical, C2-6Alkynyl, hetero C1-6Alkyl, hetero C2-6Alkenyl, hetero C2-6Alkynyl, C3-10Carbocyclic radical, C6-10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two paired RggSubstituents may be linked to form ═ O or ═ S; wherein X-is a counterion.
34. The matrix-forming agent or combination of matrix-forming agents of claim 33, wherein the polymer is of the formula:
Figure FDA0003540956370000131
wherein:
z is independently at each occurrence optionally substituted C 1-6An alkyl group;
G1Aand G2AEach independently is hydrogen; and is
p, q, r, s and t are each independently integers from 1 to 200, where the sum of p and t is at least 1 and the sum of q, r and s is at least 1.
35. The matrix-forming agent or combination of matrix-forming agents of claim 33, wherein the polymer is of the formula:
Figure FDA0003540956370000132
wherein:
p and t are each independently an integer from 1 to 200, inclusive, wherein the sum of p and t is at least 1.
36. The matrix-forming agent or combination of matrix-forming agents of claim 35, wherein the polymer is of the formula:
Figure FDA0003540956370000133
Figure FDA0003540956370000141
37. the matrix-forming agent or combination of matrix-forming agents according to any one of claims 33 to 36, further comprising a therapeutic agent.
38. The matrix-forming agent or combination of matrix-forming agents of claim 33, wherein the polymer is of the formula:
Figure FDA0003540956370000142
39. the matrix-forming agent or combination of matrix-forming agents according to claim 33, wherein p and t are each integers from 1 to 100, inclusive.
40. The matrix-forming agent or combination of matrix-forming agents according to claim 33, wherein p and t are each integers from 1 to 10, inclusive.
41. The matrix-forming agent or combination of matrix-forming agents according to claim 33, wherein r is an integer from 10 to 100, inclusive.
42. A composition according to claim 1 for use in the treatment of a disease selected from:
A) infectious diseases;
B) an otic disorder, wherein the penetration enhancer increases the flux of the antibiotic across the tympanic membrane; and wherein the matrix forming agent comprises a copolymer comprising a phosphate ester monomer; and
C) an otic disorder, wherein the penetration enhancer increases the flux of the antibiotic across the barrier.
43. The composition of claim 42, wherein the matrix former comprises a copolymer comprising a phosphate ester monomer and the copolymer further comprises a block selected from the group consisting of: polyethylene oxide, polypropylene oxide, poloxamers, poloxamer 407, poloxamer 188, poloxamine, methylcellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose, xyloglucan, acetate, phthalate, latex, polyacrylic acid, N-isopropylacrylamide, cellulose, chitosan, dextran, and hyaluronic acid, and derivatives thereof.
44. The composition of claim 42, wherein the matrix forming agent comprises a polysaccharide derivative selected from a hyaluronic acid derivative, a cellulose derivative, or a dextran derivative.
45. The composition of claim 44, wherein the matrix-forming agent comprises a polysaccharide derivative comprising a crosslinkable functional group, and wherein the crosslinkable functional group is selected from the group consisting of amine, amide, aldehyde, ester, ketone, hydroxyl, hydrazine, hydrazide, maleimide, and thiol.
46. The composition of any one of claims 1 to 32 or 42 to 45, wherein the composition forms a gel at a phase transition temperature of 0 ℃ to 37 ℃.
47. Use of the composition of any one of claims 1-32 or 42-45 in the manufacture of a medicament for treating an infectious disease in a subject in need thereof.
48. Use of the composition of any one of claims 1-32 or 42-45 in the manufacture of a medicament for treating an otic disorder in a subject in need thereof.
49. The use of claim 47, wherein the infectious disease is a bacterial infection.
50. The use according to claim 49, wherein the bacterial infection is a Haemophilus influenzae (H.influenza), Streptococcus pneumoniae (S.pneumoniae) or Moraxella catarrhalis (M.catarrhalis) infection.
51. The use of claim 47, wherein the infectious disease is otitis media.
52. Use of the composition of any one of claims 1-32 or 42-45 in the manufacture of a medicament for eradicating a biofilm in a subject in need thereof.
53. A kit for treating an otic disorder comprising a container, the composition of any one of claims 1-32 or 42-45, and instructions for administering the composition to a subject in need thereof.
54. The kit of claim 53, wherein the kit further comprises a dropper, a syringe, or a catheter; or a dual syringe.
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